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The Present and Future for Peripheral
Nerve Regeneration
Georgios N. Panagopoulos, MD; Panayiotis D. Megaloikonomos, MD; Andreas F. Mavrogenis, MD
abstract
Peripheral nerve injury can have a potentially devastating impact on a patient’s quality of life, resulting in severe disability with substantial social and
personal cost. Refined microsurgical techniques, advances in peripheral
nerve topography, and a better understanding of the pathophysiology and
molecular basis of nerve injury have all led to a decisive leap forward in the
field of translational neurophysiology. Nerve repair, nerve grafting, and nerve
transfers have improved significantly with consistently better functional outcomes. Direct nerve repair with epineural microsutures is still the surgical
treatment of choice when a tension-free coaptation in a well-vascularized
bed can be achieved. In the presence of a significant gap (>2-3 cm) between
the proximal and distal nerve stumps, primary end-to-end nerve repair often
is not possible; in these cases, nerve grafting is the treatment of choice. Indications for nerve transfer include brachial plexus injuries, especially avulsion
type, with long distance from target motor end plates, delayed presentation,
segmental loss of nerve function, and broad zone of injury with dense scarring. Current experimental research in peripheral nerve regeneration aims to
accelerate the process of regeneration using pharmacologic agents, bioengineering of sophisticated nerve conduits, pluripotent stem cells, and gene
therapy. Several small molecules, peptides, hormones, neurotoxins, and
growth factors have been studied to improve and accelerate nerve repair and
regeneration by reducing neuronal death and promoting axonal outgrowth.
Targeting specific steps in molecular pathways also allows for purposeful
pharmacologic intervention, potentially leading to a better functional recovery after nerve injury. This article summarizes the principles of nerve repair
and the current concepts of peripheral nerve regeneration research, as well
as future perspectives. [Orthopedics. 2017; 40(1):e141-e156.]
P
eripheral nerve injury is a substantial clinical problem with potentially devastating consequences
for patients. Peripheral nerve surgery is
performed annually in 100,000 patients
in the United States and Europe alone.1
In the United States, approximately $150
billion is spent annually as a result of
JANUARY/FEBRUARY 2017 | Volume 40 • Number 1
nerve injury, with the costs for injuries to
a median and an ulnar nerve estimated at
roughly $70,000 and $45,000, respectively; 87% of these costs are the result of lost
production.2
Traumatic etiologies for peripheral
nerve injury include penetrating trauma,
traction and compression, ischemia, electrocution, and vibration injuries.3 Traction-related injury secondary to a motor
vehicle accident and lacerations by sharp
objects or long bone fractures are the most
frequent mechanisms implicated in the
civilian setting4; blast injuries from explosives or gunshot wounds are the main
causes of nerve injury seen in warfare or a
hostile setting.5 Many patients treated for
peripheral nerve injury continue to exhibit
incomplete recovery in the long term, often with partial or total loss of motor, sensory, and autonomic function, as well as
intractable neuropathic pain.6
The authors are from the First Department of
Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, Athens,
Greece.
The authors have no relevant financial relationships to disclose.
Correspondence should be addressed to:
Andreas F. Mavrogenis, MD, First Department of
Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, 41 Ventouri
St, 15562 Holargos, Athens, Greece (afm@otenet.
gr).
Received: April 15, 2016; Accepted: August
23, 2016.
doi: 10.3928/01477447-20161019-01
e141
n Feature Article
nerve ends after adequate mobilization of
the proximal and distal stumps. However,
primary repair is usually possible only in
cases of clean-cut nerve transection with
minimal gap and neuronal tissue loss.
When tension-free primary nerve repair is not possible, autogenous nerve
grafting is considered the gold standard
for bridging repair of the nerve gaps. The
use of biological or artificial nerve conduits, or the application of nerve transfers
are further viable alternatives (Table 1).7,8
Following nerve repair, nerve regeneration is the goal. Current research aims to
accelerate nerve regeneration using pharmacologic agents and growth factors, stem
cell-based therapies (stem cell-derived
Schwann cells), and bioengineered nerve
conduits.4,10 This article summarizes the
principles of nerve repair and the current
concepts of peripheral nerve regeneration
research, as well as future perspectives.
Nerve Repair
Figure 1: Peripheral nerve repair treatment algorithm. Abbreviations: I-V, degrees of nerve injury according to Sunderland; NCS, nerve conduction studies; OT, occupational therapy.
Figure 2: Intraoperative photograph showing direct end-to-end repair of a superficial radial nerve
in the dorsum of the palm.
In recent years, peripheral nerve surgery has progressed substantially. Advances in microsurgical techniques and
e142
refinements in clinical management protocols, experimental research using versatile in vitro and animal models, better
understanding of the pathophysiology of
nerve injury, deeper knowledge of the internal topography of peripheral nerves and
molecular basis of neuronal growth, and
development of reproducible methods of
peripheral nerve regeneration evaluation
have improved functional outcomes.6-8
The surgical treatment strategy depends
on the type and level of injury (Figure 1).
Primary direct end-to-end microsurgical
epineural nerve repair remains the gold
standard for surgical treatment (Figure
2), and the ideal setting for direct nerve
repair is an injury zone with good blood
supply and soft tissue coverage.7,9 Primary microsurgical nerve repair involves
a tension-free, end-to-end coaptation of
Direct nerve repair with epineural microsutures is still the surgical treatment of
choice when a tension-free coaptation in
a well-vascularized bed can be achieved.
This entails gross fascicular matching
between the proximal and distal nerve
ends by lining up both the internal nerve
fascicles and the surface epineural blood
vessel patterns. Nerve suture should be
performed using an atraumatic microsurgical technique and surgical loupes or an
operating microscope for magnification.
A range of sutures is used; 6-0 and 7-0
nylon on an 8-mm vascular needle is useful for epineurial suture. Finer sutures of
8-0, 9-0, and 10-0 are used for perineurial
suturing, nerve transfer, and grafting.
The appropriate needle holders, fine
forceps, and scissors for work under the
microscope should be available. Fine skin
hooks, plastic slings, light clips, and malleable retractors are necessary. All tissues
must be treated gently. Tender tissue handling and accurate hemostasis are more
important than antibiotics for infection
prevention. Bipolar diathermy is essential.
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Table 1
Current Treatment Options When Primary Tensionless End-to-End Neurorrhaphy Is Unfeasible
Option
Indications
Pros
Cons
Nerve autografts
Gold standard for bridging irreducible nerve gaps
Bridge nerve gap, nonimmunogenic, variety of donor nerves
available
Sensory loss, scarring, neuroma formation, second incision, limited
supply, inferior to tension-free
primary repair
Nerve allografts
Reserved for devastating or segmental injury
Readily accessible, unlimited
supply, bridge nerve gap, avoid
donor-site morbidity
Potential side effects of host immunosuppression
Nerve transfers
Proximal upper limb injury,
brachial plexus reconstruction,
segmental nerve injury
Avoid donor-site morbidity, potential earlier reinnervation due
to proximity of donor nerves to
target motor end plates
Possible loss of function from donor
nerve site, donor muscle no
longer an acceptable donor for
muscle transfer
End-to-side coaptation
Proximal nerve stump unavailable
or inaccessible
Low-morbidity technique when
used for sensory defects
Motor nerve recovery only seen
after donor nerve axotomy
Nerve conduits
Short nerve defects (up to 3 cm)
Readily available, avoid donor-site
morbidity, bridge nerve gap, barrier to scar tissue infiltration, local
neurotrophic factor accumulation
Variable outcomes, lack of laminin
scaffold and Schwann cells, use
limited to short nerve gaps
The operating field should be maintained
as free of blood as possible but kept moist
by regular saline irrigation. Tourniquet
use should be kept to the bare minimum.
Other techniques for nerve repair include fascicular and grouped fascicular
repair, requiring intraneural dissection and
direct matching and suturing of fascicular
groups. This approach attempts a more
accurate approximation of regenerating
axons but requires more dissection and
potential soft-tissue disruption. Thus, the
advantage of a better fascicle alignment
comes with the cost of more surgical trauma and scarring. Although outcomes are
controversial, this technique often is used
in nerves with straightforward and consistent motor and sensory topography.9,11
Visual clues, such as surface vessels, electrical stimulation in the awake patient, and
histologic staining with acetylcholine esterase and carbonic anhydrase, have been
used to achieve better matching.12
An alternative repair technique is the
use of tissue adhesives such as fibrin glue
to either supplement or replace sutures.
This approach creates a gel-like clot that
can be applied as an adhesive cylinder
around the approximated nerve ends. This
repair strategy is efficient and easy to use,
minimizes trauma to the nerve ends, and
possibly creates a barrier to invading scar
tissue. Material intervening between nerve
ends does not seem to block nerve regeneration. The main disadvantage of this
technique is inferior holding strength.13
Nerve Grafts
In the presence of a significant gap
(>2-3 cm) between the proximal and distal
nerve stumps, primary end-to-end nerve
repair often is not possible. Such gaps can
occur in severe neurotmesis lesions such
as high-velocity gunshot wounds or in
axonotmesis stretch injuries in which long
regions of the nerve may be damaged in
the setting of a lesion-in-continuity.14 In
these cases, nerve grafting is the treatment of choice; this implies that a piece
of nerve harvested from another nerve is
sutured between the proximal and distal
stumps of the injured nerve (Figure 3).
The proximal and distal nerve stumps
are trimmed of scar tissue (bread-loafing)
until normal fascicular structure is revealed
for the nerve fascicles to be properly realigned. The trimmed nerve stumps should
be inspected for mushrooming, which
JANUARY/FEBRUARY 2017 | Volume 40 • Number 1
Figure 3: Intraoperative photograph showing repair of a median nerve laceration in the distal forearm with an autogenous nerve graft (sural nerve
graft).
stands for slight protrusion of the nerve
fascicles with concurrent retraction of the
epineurium; reaching such tissue after debridement signifies that these particular
nerve ends are suitable for suturing or graft
interposition.6 Motor and sensory fascicles
also should be properly realigned.8
Next, the nerve graft is interpositioned;
it is essential to leave some redundancy
in the repair in proximity to the sutured
proximal and distal sites. It is difficult to
give a general rule for how much tension
is acceptable in each individual case, but
if flexion of a joint is necessary to shorten
the distance between the nerve ends, the
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Table 2
Common Nerves Used as Nerve Autografts
Donor Nerve
Length, cm
Sensory Defect
Sural nerve
30-40
Dorsal aspect of lower leg and
lateral foot
Medial antebrachial cutaneous
nerve
10-12a
8-10b
Medial forearm
Lateral antebrachial cutaneous
nerve
10-12
Lateral forearm
25
Radial dorsal hand
Superficial sensory branch of the
radial nerve
a
Above elbow.
Below elbow.
b
resulting tension usually will be too great,
and further dissection or a longer graft
should be considered. Because the graft
may shrink slightly, it should be approximately 15% longer than the maximum
gap.
Nerve grafting may include autografts
and allografts. Nerve autografts are considered the gold standard in nerve repair
of irreducible nerve gaps.8 Autografts provide appropriate neurotrophic factors and
viable Schwann cells, both essential for
axonal regeneration. Many factors may
affect the choice of an autogenous nerve
graft, including the size of the nerve gap,
location of proposed nerve repair, and
associated donor-site morbidity.8 Nerve
grafts can be single, cable, trunk, interfascicular, or vascularized.15,16 The grafts are
either sutured to the epineurium of single
nerves or more commonly to the perineurium of individual fascicles, depending on
nerve caliber, type, and location.
Debridement of nerve stumps must
continue until an orderly and recognizable
architecture of bundles is displayed. The
current authors favor a grouped fascicular
repair, as the creating of multiple “fascicular fingers” may provide a better match
and alignment. Sutures should be as few
as possible, but as many as necessary to
ensure a persistently correct orientation.
Intact nerve tissue should be manipulated
as little as possible to avoid potential fi-
e144
brotic reactions. Fibrin glue is an adjunct
to reduce the total number of sutures, thus
reducing the likelihood of suture-induced
fibrosis.15,16
Nerve autografts usually are harvested
from expendable sensory nerve sites. The
sural nerve is the workhorse graft; it allows 30 cm to 40 cm of graft to be obtained from each leg. Alternative nerve
donor sites are the medial and lateral cutaneous nerves of the forearm, the dorsal
cutaneous branch of the ulnar nerve, the
superficial sensory branch of the radial
nerve, the superficial and deep peroneal
nerves, the intercostal nerves, and the posterior and lateral cutaneous nerves of the
thigh (Table 2).17 Ray and Mackinnon8
suggest the anterior branch of the medial
antebrachial cutaneous nerve is the ideal
donor for upper extremity reconstruction;
they also propose using a noncritical portion of a proximally injured nerve as an
autograft. Such examples include the third
web space fascicle of the median nerve or
the dorsal cutaneous branch of the ulnar
nerve.18
Nerve harvesting can be performed
through a single long longitudinal incision, multiple stair-step incisions, or endoscopic methods. The proximal end of
the cut nerve should be transposed proximally and buried deep to the fascia or
fat tissue to prevent neuroma formation
and pain. Long-lasting anesthesia also
can be injected directly into the nerve to
minimize discomfort. The harvested nerve
should be handled gently, denuded of excess mesoneurial tissue, and laid between
saline-soaked swabs until used.
The drawbacks of nerve autografting include sacrificing a functioning but
otherwise expendable nerve (usually sensory) for a more important injured nerve
(usually motor) and donor-site morbidity including sensory loss and scarring at
the donor site as well as the potential for
neuroma formation and pain.19 The harvested autogenous nerve graft undergoes
Wallerian degeneration and thus merely
provides mechanical guidance, creating a
supportive structure for the ingrowing axons.20 In addition, at the repair site, there
is unavoidable size and fascicle mismatch,
scarring, and fibrosis from sutures, as well
as damage from tissue handling. All of
these factors, jointly with the injury itself,
may lead to poor regeneration.21
An alternative to autogenous nerve
grafting is the use of nerve allografts.
Nerve allografts are readily accessible,
offer an unlimited supply of neuronal tissue, and are not associated with donor-site
morbidity. However, nerve allografts require systemic immunosuppression; this
fact, as well as the increased cost of allografts, represent potential drawbacks to
nerve repair with nerve allografts.22 Several techniques have been used to reduce
allograft antigenicity, such as cold preservation, irradiation, and lyophilization.22
Furthermore, it has been observed that
once adequate host Schwann cell migration has occurred into the nerve allograft
at approximately 24 months after nerve
repair, systemic immunosuppression can
be withdrawn.8 Also, despite the morbidity of immunosuppressive therapy, a commonly used immunosuppressive agent
(FK506, tacrolimus [Prograf]; Astellas
Pharma US Inc, Northbrook, Illinois) has
been demonstrated to further enhance peripheral nerve regeneration.19,23,24
To avoid immunosuppression, nerve allografts are decellularized by a process of
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Table 3
Common Nerve Transfers
Injured Nerve
Missing Function
Donor Nerve
Recipient Nerve
Motor
Suprascapular
Shoulder abduction, external rota- Distal spinal accessory
tion
Suprascapular
Long thoracic
Scapular stabilization, forward ab- Medial pectoral, thoracodorsal, induction
tercostal
Long thoracic
Axillary
Shoulder abduction
Triceps branch of radial nerve, medial pectoral
Axillary
Musculocutaneous
Elbow flexion
Ulnar nerve fascicle to FCU; median Brachialis branch; biceps branch
nerve fascicle to FCR, FDS
Spinal accessory
Shoulder elevation and abduction
Medial pectoral, C7 redundant fascicle
Spinal accessory
Ulnar
Intrinsic hand
Terminal AIN (branch to pronator
quadratus)
Ulnar nerve fascicles to deep motor
branch
Median
Thumb opposition
Terminal AIN (branch to pronator
quadratus)
Median (recurrent) motor
Finger flexion
FCU, brachialis
AIN
Pronation
ECRB, FCU, FDS
Pronator branch
Elbow, wrist, and finger extension
FCR, FDS±PL
ECRB and PIN
Radial
Sensory
Median sensory
Ulnar sensory
Thumb-index key pinch area sensa- Ulnar common sensory branch to
tion
4th web space
Median common sensory branch to
1st web space
Dorsal sensory branch of the ulnar
nerve
Median common sensory branch to
1st web space
Median common sensory branch to
the 3rd web space
Ulnar common sensory branch to
the 4th web space; ulnar digital
nerve to the small finger
Lateral antebrachial cutaneous
Dorsal sensory branch of the ulnar
nerve
Ring and small finger sensation
Abbreviations: AIN, anterior interosseous nerve; ECRB, extensor carpi radialis brevis; FCR, flexor carpi radialis; FCU, flexor carpi ulnaris;
FDS, flexor digitorum superficialis; PIN, posterior interosseous nerve; PL, palmaris longus.
chemical detergent, enzyme degradation,
and irradiation, resulting in an acellular
nerve scaffold. The advantage of decellular nerve allografts compared with hollow
nerve conduits is that the internal nerve
structure including endoneurial tubes,
basal lamina, and laminin remain intact,
maintaining a structural environment ideal
for axonal regeneration.11 Currently, there
is only 1 commercially available decellular nerve allograft (Avance Nerve Graft;
AxoGen Inc, Alachua, Florida). Although
many believe that these nerve allografts
may have a longer “critical gap depth,”
research currently supports their use for
small diameters (1-2 mm) and short gap
lengths (up to 30 mm).25
Nerve Transfers
The concept of nerve transfer is not
new, but it recently has been revived and
has gained significant momentum. A nerve
transfer is the surgical coaptation of a
healthy nerve donor to an injured nerve.26
The concept of nerve transfer is similar to
that of tendon transfer, with an essential
distal function being recovered at the expense of a secondary function. Similarly,
a nerve transfer converts a proximal injury
into a distal one by transferring a nearby
JANUARY/FEBRUARY 2017 | Volume 40 • Number 1
redundant nerve function to a distal denervated nerve close to the target.8 Indications for nerve transfer include brachial
plexus injuries, especially avulsion type
with long distance from target motor end
plates, delayed presentation, segmental
loss of nerve function, and a broad zone
of injury with dense scarring.27
Among the most popular goals for reinnervation via nerve transfer are elbow
flexion, shoulder abduction, scapular stabilization, elbow extension, and distal motor
transfers (Table 3).26 Elbow flexion can be
restored with a double fascicular transfer
of ulnar or median nerve fascicles to the
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biceps. For shoulder abduction, the spinal
accessory nerve can be transferred to the
suprascapular nerve. Scapular stabilization
can be achieved by transferring the thoracodorsal nerve to the long thoracic nerve.
Transfer of the distal anterior interosseous
nerve to the ulnar nerve can restore some
intrinsic muscle function of the hand.26,27
The benefits of nerve transfers are well
established8,27,28: nerve transfers avoid
autografts and associated donor-site morbidity; proximity of donor nerves to target
motor end plates provides earlier reinnervation; in most cases, there is only 1
neurorrhaphy site instead of 2, as in nerve
grafts; neurorrhaphy and dissection are
performed in uninjured and unscarred tissue beds; original muscle biomechanics
remain unaltered; and more rapid nerve
recovery and motor reeducation usually is
possible. Disadvantages include possible
loss of function in the donor nerve site, as
well as the fact that the donor muscle is
no longer an acceptable donor for muscle
transfer.8,27,28
A reemerging concept similar to nerve
transfer is end-to-side coaptation or neurorrhaphy.8,29 This technique, described
as early as 1873, subsequently was abandoned and revived in the early 1990s after the successful report of Viterbo et al.30
End-to-side neurorrhaphy is indicated
when the proximal stump of the injured
nerve is not available or is inaccessible;
instead of nerve repair or grafting, which
is not applicable, the distal stump of the
injured nerve is coaptated to the side of
an uninjured donor nerve. The rationale
is that collateral axonal sprouting from a
healthy nerve can invade the stump of an
injured nerve, when the 2 are sutured together in an end-to-side fashion.31
Although no randomized clinical trials have been performed, current literature includes a number of case reports
and small case series on different clinical
applications, including sensory nerve lesions, brachial plexus lesions, facial nerve
injuries, mixed nerve lesions, and painful
neuromas.32 The results have been con-
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troversial; current evidence shows that
collateral sprouting occurs more consistently in sensory fibers, with or without
development of a perineural window. In
contrast, motor sprouting following endto-side neurorrhaphy requires axonotomy
to be done to the donor nerve.33 Therefore,
pending further refinement of end-to-side
neurorrhaphy, this procedure should not
substitute for standard techniques in most
cases. Instead, it can be considered a valid
therapeutic option in selected situations,
such as for reconstruction of noncritical
sensory deficits, in combination with other
strategies in cases of failure of other previous attempts of nerve repair, or whenever
other approaches are not feasible.8,29
Terzis and Tzafetta34 first described the
reverse end-to-side neurorrhaphy named
the “babysitter procedure” in 1984. They
dissected a normal motor fascicle from
the hypoglossal nerve and transferred it to
the side of an injured, in-continuity facial
nerve to gain some reinnervation of the
facial musculature while awaiting cross
facial nerve grafting. Davidge et al35 referred to this procedure as a supercharged,
end-to-side neurorrhaphy and reported
encouraging results in both laboratory and
clinical studies.
Pharmacologic Agents
Currently, there are no clinically available pharmacologic methods to enhance
nerve regeneration. Nevertheless, several small molecules, peptides, hormones,
neurotoxins, and growth factors have
been studied and suggested as potential
candidates to improve and accelerate
nerve repair and regeneration by reducing neuronal death and promoting axonal
outgrowth.36 Recent advances in molecular biology have indicated that targeting
specific steps in molecular pathways may
allow for purposeful pharmacologic intervention, potentially leading to a better
functional recovery after nerve injury.36
Experimental studies have shown that
major molecular pathways implicated in
neuron survival and neurite outgrowth
include PI3K (phosphatidylinositol-3 kinase)/Akt (protein kinase B) signaling cascade, Ras-ERK (rat sarcoma-extracellular
signal-regulated kinase) pathway, the cyclic adenosine monophosphate (cAMP)/
protein kinase A (PKA), and Rho–ROK
signaling.36 Various molecules, otherwise
frequently used in a totally different clinical setting, have been studied for their potential influence in the nerve regeneration
process; among these are erythropoietin
(EPO),37 tacrolimus (FK506),38 acetyl-Lcarnitine (ALCAR),39 N-acetylcysteine
(NAC),40 ibuprofen,41 melatonin,42 and
transthyretin43 (Table 4).44-48
The PI3K/Akt signaling cascade provides trophic support for neurons, blocks
apoptosis, and mediates growth, differentiation, and directional signaling.49
The Ras-ERK pathway is a key promoter
of neurite outgrowth and also has been
found to enhance axonal survival.49 The
cAMP/PKA pathway has been implicated
in neuronal outgrowth and survival, differentiation, and guidance, both in vitro
and in vivo.50 Agents acting on this pathway used in nerve regeneration research
include rolipram and testosterone.36 In
the Rho–ROK signaling pathway, Rho
GTPases mediate the response of growth
cones to extracellular ligands and serve to
link them to the actin cytoskeleton, either
positively or negatively modulating neurite outgrowth.51 Agents acting on this signaling pathway include fasudil, ibuprofen,
and proteoglycan digesting enzyme chondroitinase ABC.36
A striking example of how a substance,
normally used in another clinical setting,
can actually have a substantial effect on
peripheral nerve regeneration is represented by the immunosuppressant agent tacrolimus (FK506). FK506 is a macrocyclic
lactone produced by the bacterium Streptomyces tsukubaensis, isolated in 1984
from a soil sample in Tsukuba, Japan.52
Currently, FK506 is an FDA-approved
immunosuppressant used in prevention of
allograft reject after liver, kidney, and other solid organ transplantation. It has been
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Table 4
Pharmacologic Agents Shown to Enhance Nerve Regeneration
Agent/Key Reference
37
Clinical Use/Properties
Mechanism of Action
Observed Effects
Erythropoietin
Anemia in CRF
CGRP increased; activation of PI3K/
Akt, JAK–STAT, and NFkB signaling
pathways
Sensory axonal density and caliber
increased; improved motor axonal
outgrowth; downregulation of injury
markers in central perikarya
Tacrolimus (FK506)38
Prevention of organ rejection after transplant
Activation of ERK via FKBP-52 and
Hsp-90 binding; calcineurin inhibition; activation of GAP-43 and
TGF-ß1; induces SC proliferation
and myelin debris removal
Number of myelinated axons, myelin
thickness, and axon sprouting
increased; neuroprotection; rate of
axon regeneration increased
Geldanamycin44
Originally developed as a
chemotherapeutic agent
Binds Hsp-90, activating ERK and
GAP-43
Rate of axon regeneration increased;
functional recovery increased
Acetyl-L-carnitine39
Natural antioxidant
Neurotrophins increased, TKA and
ERK 1/2; apoptotic proteins (eg,
caspase-3) decreased
Enhanced survival; myelin thickness
and axon number and diameter
increased
N-acetylcysteine40
Mucolytic, acetaminophen
antidote, prevents contrast
toxicity
Activates Ras–ERK and JAK–STAT; upregulates Bcl-2 mRNA; downregulates Bax and caspase-3 mRNA
Neuronal death decreased; promoted
sensory nerve regeneration
Rolipram45
N/A
PDE-5 inhibition
Prevents cAMP decrease; myelination
and neuron number across repair site
increased
Testosterone46
Hormone
GFAP and HSP decreased, BDNF
expression increased; upregulates
RAGs (ßII-tubulin and GAP-43)
Axon regeneration rate increased
Fasudil47
SAH treatment in Japan
Prevents collapse of growth cones
Nerve fiber number, density, and
width increased; number of large
myelinated axons increased; improved sensory neurite outgrowth
Chondroitinase ABC48
Enzyme that degrades proteoglycans
Degrades chondroitin sulfate proteoglycans, inactivates RhoA
Regeneration of motor and sensory neurons across the repair site
increased
Ibuprofen41
NSAID
Inhibits RhoA cascade
Area and thickness of myelinated axons
increased
Melatonin42
Hormone; regulates circadian rhythm
TGF-ß1 and bFGF decreased; SOD
increased
Collagen production and neuroma
formation, antioxidant properties
decreased
Transthyretin43
Serum carrier of thyroxine
and retinol; called prealbumin
Unknown
Neurite number and length increased
Abbreviations: Akt, protein kinase B; Bax, Bcl-2 associated X protein; Bcl-2, B-cell lymphoma 2; BDNF, brain-derived neurotrophic factor;
bFGF, basic fibroblast growth factor; cAMP, cyclic adenosine monophosphate; CGRP, calcitonin gene-related peptide; CRF, chronic renal failure;
ERK, extracellular signal-regulated kinase; FKBP-52, FK506 binding protein 52; GAP-43, growth-associated protein 43; GFAP, glial fibrillary
acidic protein; HSP, heat shock protein; Hsp-90, heat shock protein 90; JAK–STAT, Janus kinase–signal transducer and activator or transcription;
N/A, not applicable; NFkb, nuclear factor k-light-chain-enhancer of activated B cells; NSAID, nonsteroidal anti-inflammatory drug; PDE-5,
phosphodiesterase-5; PI3K, phosphatidylinositol-3 kinase; RAGs, regeneration-associated genes; Ras–ERK, rat sarcoma-extracellular signalregulated kinase; SAH, subarachnoid hemorrhage; SC, Schwann cells; SOD, superoxide dismutase; TGF-ß1, transforming growth factor ß 1;
TKA, tyrosine kinase A.
found to have a 10 to 100 times stronger
immunosuppressant effect than cyclosporine-A, with fewer side effects.53
Interestingly, FK506 was found to enhance nerve regeneration by increasing
axonal outgrowth and inducing Schwann
cell proliferation (Figure 4).54 The exact
mechanism of its neuroregenerative effect remains unclear; many suggest that
binding to FKBP-12 and inhibiting cal-
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cineurin, as well as increasing expression of growth associated protein 43
(GAP-43) and transforming growth factor beta 1 (TGF ß-1), may be some of the
implicated mechanisms.24 Other studies
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Figure 5: Intraoperative photograph showing direct end-to-end repair with placement of a nerve
conduit protector for a median nerve laceration in
the wrist.
Figure 4: Intraoperative photographs showing
complete transection of the left sciatic nerve in a
rat (A), nerve repair with a 1-cm nerve gap using a
collagen-based nerve conduit (B), and injection of
FK506 into the nerve gap for acceleration of nerve
repair (C).
have examined the ideal dosing, timing,
and route of administration of FK506,24
aiming to bioengineer a local release delivery system that would avoid potential
systemic side effects related to immunosuppression.55
As most of the aforementioned pharmacologic agents have been tested only
in cell culture or animal models, this field
is still in its infancy. As researchers gain
insight to new molecular pathways, new
potential molecular targets and novel therapeutic options will emerge for patients
with nerve injury.
Nerve Conduits
Autograft scarcity, donor-site morbidity, potential for donor-site neuroma formation, and suboptimal outcomes have driven
increasing efforts to seek viable alternatives to autologous nerve grafts during the
e148
past few decades.56 A way to circumvent
these issues is the use of biological or synthetic nerve guidance channels, or simply
nerve conduits. A nerve conduit is a tubular
structure designed to bridge the gap of a
sectioned nerve that is not amenable to primary end-to-end neurorrhaphy, to protect
the nerve from the surrounding tissue and
scar formation, and to guide the regenerating axons into the distal nerve stump (Figure 5).56 Currently, several nerve conduits
are available (Table 5), with diameters
ranging from 1.5 to 10 mm. Clinical use
presently is limited to the repair of relatively small nerve defects (<3 cm) in smallcaliber digital nerves and as a nerve repair
wrapping material.57
The key concept behind the use of nerve
conduits is that guidance to nerve regeneration is provided not only by a mechanical
effect (conduit lumen and wall), but also
by a chemical effect (accumulation of neurotropic and neurotrophic factors), thus
favorably conditioning the nerve injury microenvironment.56 This process ultimately
permits the formation of new extracellular
matrix over which fibroblasts, blood vessels, and Schwann cells can migrate and
provide the circumstances for successful
nerve regeneration.56
Although materials vary considerably,
the technique of nerve conduit preparation and positioning is generally the same.
The chosen conduit, slightly larger than
the nerve in question, usually is soaked in
normal or heparinized saline prior to use.
Then, the conduit is stabilized to the surrounding soft tissues by means of 2 or 3
anchoring interrupted sutures to facilitate
nerve stump insertion. Next, the conduit
is sewn in a U-shaped fashion on itself to
create the desirable lumen. Finally, both
nerve stumps are inserted 2 mm into the
conduit and fixed via 2 or 3 epineural sutures (8-0 or 9-0 nylon). Saline is injected
into the conduit to prevent clot formation
and lumen blockage.56
Nerve conduits can be biological (autogenous and nonautogenous) and synthetically fabricated (absorbable and
nonabsorbable).56 Biological autogenous
nerve conduits include arteries, veins,
muscle, tendon, and epineural sheath.
Although experimental use and small
case studies have yielded occasionally
promising results, their clinical use is not
currently recommended.56,58 Biological
nonautogenous nerve conduits include
type I collagen such as NeuraGen (Integra
LifeSciences Co, Plainsboro, New Jersey)
or NeuroFlex (Collagen Matrix Inc, Oakland, New Jersey), gelatin (a protein deriving from collagen), silk fibroin, and polysaccharides such as chitosan, alginate, and
agarose hydrogel-based conduits.59-61
Collagen is advantageous as it is abundant, easily isolated and purified, shows
adhesiveness for different cell types, and
has been demonstrated to be effective both
in vitro and clinically. A key limitation
is the variable time needed for complete
biodegradation, ranging from 8 months
(NeuroFlex) to 48 months (NeuraGen),
potentially leading to nerve compression.62
Synthetic absorbable nerve conduits include aliphatic polyesters and copolyesterbased conduits such as polyglycolic acid,
polylactic acid, poly(epsilon-caprolactoneco-lactide), polycaprolactone, and polyvinyl alcohol.4,63 Synthetic nonabsorbable
nerve conduits include silicone and expanded polytetrafluoroethylene (ePTFE,
Gore-Tex; W. L. Gore & Associates, Inc,
Newark, Delaware) conduits.64,65
In an attempt to enhance nerve conduit
efficacy and to extend operational distance
in nerve regeneration, the concept of introducing luminal additives into conduits also
Copyright © SLACK Incorporated
n Feature Article
Table 5
Commercially Available FDA-Approved Nerve Conduits
Product
Name
Material
Structure
Manufacturer
FDA
Clearance
Length,
cm
NeuraGen
Collagen type I
Semipermeable,
fibrillar collagen
structure
Integra LifeSciences
Co (http://www.
integra-ls.com)
June 2001
2-3
NeuroFlex
Collagen type I
Flexible, semipermeable tubular collagen matrix
Collagen Matrix Inc
(http://www.
collagenmatrix.com)
September
2001
2.5
NeuroMatrix
Collagen type I
Semipermeable tubular collagen matrix
Collagen Matrix Inc
September
2001
2.5
NeuraWrap
Collagen type I
Longitudinal slit
in a tubular wall
structure
Integra LifeSciences
Co
July 2004
2-4
NeuroMend
Collagen type I
Semipermeable
collagen wrap that
unrolls and self-curls
Collagen Matrix Inc
July 2006
2.5-5
Neurotube
PGA
Absorbable woven
PGA mesh tube
Synovis Micro Companies (http://www.
synovismicro.com)
March
1995/1999
2-4
Neurolac
PLCL
Tubular structure
Polyganics (http://
www.polyganics.
com)
October
2003/2005
3
Salutunnel
PVA
Tubular structure
Salumedica LCC
August
2010
6.35
Nerve Repair
Digital nerves; lingual and inferior alveolar nerves; brachial
plexus birth palsy; median,
ulnar, radial, posterior interosseous, common digital, and
superficial radial nerves
Spinal accessory, median, ulnar,
facial, and digital nerves
Digital nerves
Abbreviations: FDA, Food and Drug Administration; PGA, polyglycolic acid; PLCL, poly(epsilon-caprolactone-co-lactide); PVA, polyvinyl
alcohol.
has been explored.66 Cellular components
(Schwann cells, bone stromal cells, and
fibroblasts), structural components (fibrin,
laminin, and collagen), and neurotrophic
factors (fibroblast growth factor, nerve
growth factor [NGF], glial growth factor,
ciliary neurotrophic factor, vascular endothelial growth factor, glial cell-line derived
neurotrophic factor, and neurotrophin-3)
have been thoroughly investigated in vitro
with encouraging results (Table 6).67-83
Currently, nerve conduits represent
a viable alternative to autologous nerve
grafting only in selected clinical situations. In the near future, tissue-engineered
conduits enriched with neurotrophic
factor-delivery systems and cellular
components, alone or in combination,
are expected to be introduced in clinical
practice. Developing nerve conduits for
ever-longer gaps is another challenge to
overcome.
Stem Cells
Stem cells have been shown to have
the potential to help regenerate lost neurons, increase glial support cells and make
the microenvironment around the nerve
injury site more favorable.84,85 As autologous Schwann cell culture is impractical,
stem cells differentiated into a Schwann
cell-like phenotype can aid with axonal
guidance and remyelination, enhanced
growth factor, and extracellular matrix
production.85 The selection of the ideal
stem cells has been long debated in the
field of regenerative medicine; stem cells
should be easily accessible, expand rapidly in culture, be able to survive in vitro and integrate into host tissue, and be
JANUARY/FEBRUARY 2017 | Volume 40 • Number 1
amenable to transfection and expression
of exogenous genes.86
Stem cell differentiation for nerve regeneration is an argument. Stem cells
may be transplanted at the injury site as
they are in their undifferentiated state,
or they can undergo a short period of in
vitro differentiation into Schwann celllike cells. The latter can be achieved with
stem cell exposure to ß-mercaptoethanol,
all-trans retinoic acid, fetal bovine serum, forskolin, recombinant human basic fibroblast growth factor, recombinant
human platelet-derived growth factor-A,
and heregulin ß-1.87 However, the necessity of stem cell differentiation currently
is debated. Some authors maintain that
it only incurs an unnecessary delay, as
neuronal differentiation partially reverts
in vivo to the original phenotype.88 In ad-
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Table 6
Luminal Additives in Nerve Conduits for Nerve Repair
Category/Key References
Cellular66-69
Structural70-75
Neurotrophic76-80
81,82
Combined
Additives
Conduits
Animal Model
Gap Length, mm
SC (syngeneic)
PLGA
Rat sciatic
20
SC
AVNC
Rabbit tibial
40
SC (autologous)
Silicone
Rat sciatic
10
SC (allogeneic)
PLA
Rat sciatic
12
SC (lacZ transduced)
PHB
Rat sciatic
10
SC (syngeneic)
Collagen
Rat sciatic
20
EMSC
Autologous muscle
Rat sciatic
20
Fibroblast-like MSC
Silicone
Rat sciatic
15
NSC
Chitosan-coated PDMS
Rat sciatic
10
Fibrin gel
Bioabsorbable polymer
Rat sciatic
10
Laminin
PGA
Canine peroneal
80
Laminin
Polysulfone
Rat sciatic
10
Collagen
Silicone
Rat sciatic
5
Fibronectin
PHB
Rat sciatic
10
Spider silk fibers
Vein
Rat sciatic
20
Bioglass 45S5
Silastic
Rat sciatic
5
NGF
Silicone or PPE
Rat sciatic
10
NT-3
PHEMA-MMA hydrogel
Rat sciatic
10
GDNF
Silicone
Rat sciatic
13
aFGF
PHEMA-MMA hydrogel
Rat sciatic
10
bFGF
Heparin/alginate hydrogel
Rat sciatic
10
CNTF
Silicone
Rat sciatic
10
VEGF
Silicone
Rat sciatic
10
IGF-1
Autologous nerve grafts or acellular
ECM
Rat sciatic
20
PDGF
Silicone
Rat sciatic
8
Laminin and NGF
Polysulfone
Rat sciatic
10
Laminin and NGF
Polysulfone
Rat sciatic
20
Fibrin, SC, and dMSC
PHB
Rat sciatic
10
Abbreviations: aFGF, acidic fibroblast growth factor; AVNC, autogenous venous nerve conduit; bFGF, basic fibroblast growth factor; CNTF, ciliary
neurotrophic factor; dMSC, differentiated mesenchymal stem cells; ECM, extracellular matrix; EMSC, ectomesenchymal stem cells; GDNF, glial
cell-line derived neurotrophic factor; IGF-1, insulin-like growth factor 1; MSC, mesenchymal stem cells; NGF, nerve growth factor; NSC, neural
stem cells; NT-3, neurotrophin-3; PDGF, platelet-derived growth factor; PDMS, polydimethylsiloxane; PGA, polyglycolic acid; PHB, poly-3hydroxybutyrate; PHEMA-MMA, poly(2-hydroxyethyl methacrylate-co-methyl methacrylate); PLGA, poly(lactic-co-glycolic acid); PLA, polylactic
acid; PPE, poly(phosphoester); SC, Schwann cells; VEGF, vascular endothelial growth factor.
dition, undifferentiated stem cells seem to
demonstrate equally good results and also
may undergo in vivo differentiation in response to local stimuli.67
Stem cell preferred tissue harvest is another argument. Since their discovery, stem
cells have been harvested from a variety of
e150
tissues including embryonic, fetal, neural,
bone marrow, adipose tissue, skin, hair follicles, and dental pulp (Table 7).85,86,89-105
Reprogramming of somatic cells to induced
pluripotent stem cells following ectopic coexpression of transcription factors also has
been described.106 Embryonic stem cells
were first isolated from human blastocysts
in 1998.107 They can form derivatives of all
3 embryonic germ layers and have great
differentiation potential and long-term proliferation capacity.85 However, their neural
differentiation is challenging. Furthermore,
possible immunogenicity and tumorigenic-
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Table 7
Types of Stem Cells Studied for Acceleration of Nerve Regeneration
Stem Cell Source/
Key References
Animal Model
Scaffold
Delivery System
Differentiation
Rat sciatic
Culture medium
Epineurium natural
conduit
Yes
Differentiated into SC after 3
months
Mouse sciatic
Matrigel
Direct microsphere
injection
No
Better SFI, CMAP, and histology
Rat sciatic
PBS
Direct injection
into gastrocnemius
muscle
Yes
New NMJ observed in treated
muscle; benefit lost after 21 days
Rat sciatic
Fibrin glue
Direct injection
in situ
No
Myelination and motor recovery
better if used with G-CSF
Rat sciatic
Matrigel
Direct injection
in situ
No
Better results when GDNF modified
Rat sciatic
Culture medium
Seeded onto PCL
wrap
Yes
Increased myelin thickness and better functional recovery
Rabbit facial
Collagen sponge
Chitosan conduit
No
NSC+NGF group superior to NGF
alone; comparable to autograft
Pig nervis
cruralis
Neurosphere
Autologous vein
No
NSC group had superior EMG
results
Rat sciatic
Culture medium
Direct injection
No
12 of 45 rodents developed neuroblastomas
Mouse sciatic
Culture medium
Injection in situ
Both
Rat sciatic
PBS
Collagen conduit
Yes
SFI and CMAP better in conduits
filled with SDSC
Hair follicle100
Mouse sciatic
Culture medium
Injection in situ
No
HFSC differentiated into SC-like
cells; gastrocnemius contraction
improved
Dental pulp101
Rat DRG in
vitro
Culture medium
Collagen gel
Yes
hDPSC differentiated to SC-like
cells; able to support DRG neurite
outgrowth
Rat facial
Matrigel
Silicone conduit
Both
Embryonic89-91
Fetal92-94
Neural95-97
Skin98,99
Bone marrow102,103
Adipose86,104
Induced pluripotent105
Outcomes
SKP induced into SKP-SC
Better histologic and functional
outcomes than controls
Rat sciatic
Fibrin glue
ANA
No
Survival of BMSC within fibrin glue
Rat sciatic
Culture medium
Fibrin glue
Yes
Greater axon and fiber diameter;
comparable to autograft
Rat facial
Matrigel
Decellularized allogeneic artery
Yes
Results inferior to autograft
Mouse sciatic
Microsphere into
conduit
PLA/PCL conduit
Yes
Results inferior to autograft
Abbreviations: ANA, acellular nerve allograft; BMSC, bone marrow-derived mesenchymal stem cells; CMAP, compound muscle action potential;
DRG, dorsal root ganglia; EMG, electromyography; G-CSF, granulocyte colony-stimulating factor; GDNF, glial cell-derived neurotrophic factor;
hDPSC, human dental pulp stem cells; HFSC, human fetal-derived stem cells; NGF, nerve growth factor; NMJ, neuromuscular junction; NSC,
nerve stem cells; PBS, phosphate-buffered saline; PCL, poly-epsilon-caprolactone; PLA, polylactic acid; SC, Schwann cells, SDSC, skin-derived
stem cells; SFI, sciatic functional index; SKP, skin-derived precursors.
ity, as well as potential ethical controversy,
represent disadvantages hindering their
clinical applications.85
Fetal stem cells can be harvested from
amniotic membrane and fluid, umbilical
cord cells and blood, and Wharton’s jelly.
As these tissues are commonly discarded after birth, they are abundant in supply. However, the use of autogenous cells after injury
is impractical; on the other hand, allogeneic
JANUARY/FEBRUARY 2017 | Volume 40 • Number 1
cells may demonstrate clinically relevant
immunoreactivity. Widespread banking of
fetal products may obviate this obstacle.85
The same lack of autogenous supply
also is valid in the case of stem cells de-
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rived from hair follicles and dental pulp,
still restricting their use in the experimental setting.85 Skin-derived precursors
reside in the dermis, are easily accessible
and expandable in culture, and demonstrate a behavior similar to pluripotent
neural crest cells. They also have been
shown to have positive effects on nerve
regeneration.98
Nerve stem cells were first isolated
from adult murine brain in the early
1990s.108 They naturally differentiate into
neurons and glial cells, but this occurs almost exclusively during embryogenesis
or in limited locations in the central nervous system after injury.109 Even though
initially promising, their use has been
limited due to harvesting difficulties and
high rates of neuroblastoma tumorigenesis.85
Stem cells derived from bone marrow
are readily accessible, have no potential
ethical concerns, and are more clinically
applicable than embryonic stem cells and
neural stem cells. However, harvesting is
invasive and painful, and their proliferation capacity and differentiation potential
are inferior.85
Particular attention has been given to
adipose-derived stem cells. Adipose tissue contains a stromal population known
as the stromal vascular fraction, which
can be isolated by centrifugation of collagenase-digested adipose tissue.110 It has
been shown that cultured stromal vascular
fraction can give rise to multipotent precursor cells.111 In addition, adipose tissue
is easily harvested, and donor age and
harvesting site do not seem to influence
the therapeutic effect of the derived stem
cells.112 In light of their easier harvest, superior stem cell fraction, differentiation
potential, and proliferation capacity, adipose-derived stem cells have supplanted
stem cells derived from bone marrow and
are considered the preferred option for
preclinical studies.85
Stem cell method of delivery is another concern in stem cell research. Stem
cells may be injected directly around
e152
nerve stumps or a bridging nerve graft,
injected into the lumen of a nerve conduit,
suspended in a scaffold, injected into a
neuromuscular junction, or administered
systemically. Future research likely will
focus on stem cells injected systemically
with the ability to specifically target and
support the injury site.85
Gene Therapy
Gene therapy can be defined as the introduction of a foreign therapeutic gene
into living cells to treat a disease.113 This
foreign gene is termed a transgene, whose
expression is driven by a so-called promoter. The most efficient way to insert a
transgene into a cell is with the use of a
viral vector. This is a specially modified
virus that has lost its capacity to replicate
but maintains the ability to attach to and
enter into cells, delivering a transgene to
the cell nucleus.113
Studied potential vectors include herpes
simplex, adenovirus, lentivirus, and adenoassociated viral vectors.114 Of these, adenoassociated viral vectors have been shown
to be the most reliable as a gene delivery
platform.115 The main targets for gene therapy in peripheral nerve injury are Schwann
cells, fibroblasts, and denervated muscle.
The aim of gene therapy is to obtain a sort
of transcriptional reprogramming so that
more neurotrophic factors, cell adhesion
or extracellular matrix molecules, and transcription factors are produced. As gene delivery technology approaches a state of clinical readiness, the time when gene therapy
will become an integral part of the armory
of nerve surgeons is fast approaching.
Other Research Areas
Low-intensity electrical stimulation
has been shown to improve nerve regeneration, probably due to an increased production of brain-derived neurotrophic factor (BDNF) and NGF, and a subsequent
enhancement of myelin production.116
Low-power laser phototherapy also has
been studied extensively both in vitro
and in vivo.117 Finally, the future poten-
tial of olfactory ensheathing cells as an
adjunct to peripheral nerve regeneration
is promising. Olfactory ensheathing cells
are specialized glial cells, which support
axons that leave the olfactory epithelium
and project through the olfactory nerve
system into the olfactory bulb of the central nervous system. They are pluripotent,
displaying Schwann cell and astrocytelike properties. They possess the ability
to phagocytose degenerating axons, create
channels to guide new axon regeneration
and produce a variety of neurotrophic factors, including NGF, BDNF, platelet-derived growth factor, and neuropeptide Y,
enhancing injured axon survival.118
Overview of Clinical Outcomes
The past few decades have seen a shift
from nerve repair or grafting in proximal
injuries toward nerve transfer. In distal
nerve injuries, however, nerve repair and
grafting generally are more appropriate.
Patient outcome and recovery are correlated to the method and timing of nerve
repair. Comparing clinical outcomes in
peripheral nerve surgery is problematic.
The multitude of treatments available,
the multitude of injured nerves, the different degrees of nerve injury, and the
often inconsistent timing of repair are
factors that make the construction of a
well-conducted and reproducible study
a difficult endeavor, hence, the relative
lack of meaningful comparative studies or randomized trials. Most outcome
studies report the application of a given
technique in a variable number of patients. More numerous well-constructed
and well-executed studies should be performed in the near future to obtain meaningful results that would have a strong
impact on clinical practice.
In a recently published case series,
Karabeg et al119 reported the clinical outcomes of ulnar nerve grafting in 48 patients with a mean age of 32.4 years. The
graft length, level of injury, and denervation time significantly influenced the functional outcome in both motor and sensory
Copyright © SLACK Incorporated
n Feature Article
recovery. Better results were obtained in
patients with an autograft length of up to
5 cm, those who underwent surgery within 6 months after injury, and those with
distal lesions. Ozmen et al120 reported the
clinical outcomes of facial nerve grafting
in 155 patients; preoperative deficit duration was the only significant factor that affected prognosis. Okazaki et al121 reported
the outcomes of axillary nerve injury
treated with nerve grafting in 36 patients.
They concluded that nerve grafting to the
axillary nerve is a reliable method of regaining deltoid function when the lesion
is distal to its origin from the posterior
cord.
Clinical outcomes with conduits overwhelmingly regard small nerves. Weber et
al122 performed a prospective randomized
trial of polyglycolic acid conduits in digital
nerve repair compared with standard repair
in 98 patients with 136 nerve lacerations.
After 1 year of follow-up in 77 nerves,
the authors reported that in nerve gaps of
4 mm or less and in nerve gaps of 8 mm
or greater, the conduits performed better
than standard repair techniques. Haug et
al123 studied 45 digital nerve defects in 35
patients with 1-year follow-up using collagen tubes. Outcomes were reported as a
cumulative score of sensory functions with
the following results: very good in 4 cases,
good in 21 cases, mediocre in 14 cases, and
bad in 3 cases. A prospective randomized
study evaluating poly (dl-lactide-epsiloncaprolactone) (Neurolac; Polyganics,
Groningen, The Netherlands) tubes concluded that regeneration was equivalent in
digital nerve repairs with Neurolac versus
standard repair techniques in nerve gaps of
up to 20 mm.124
There are also a few clinical studies
available on AxoGen’s decellularized allograft. Karabekmez et al125 at the Mayo
Clinic reported on 10 sensory nerve reconstructions in 7 patients. Mean follow-up
time was 9 months, with an average gap
of 2.23 cm. They achieved an average of
4.4-mm moving and 5.5-mm static 2-point
discrimination. Despite the lack of a con-
2. Taylor CA, Braza D, Rice JB, Dillingham T.
The incidence of peripheral nerve injury in
extremity trauma. Am J Phys Med Rehabil.
2008; 87(5):381-385.
trol group, their study validated the role
for acellular allografts in defects up to 3
cm in length and showed reasonably good
results. Brooks et al126 reviewed the use of
acellular allografts with data from 25 surgeons at 12 centers reporting on 132 nerve
injuries, with complete data for 76 of the
repairs. These repairs included 49 sensory, 18 mixed, and 9 motor nerves with
nerve gaps up to 50 mm; findings indicated
meaningful recovery was accomplished in
87% of these cases.
The data on nerve transfers in brachial
plexus reconstruction for shoulder and
elbow function have shown outcomes
to be reliably equal or better than traditional proximal graft reconstruction and
with faster reinnervation in many cases.
Ray et al127 studied the use of double fascicular nerve transfer to the biceps and
brachialis muscles after brachial plexus
injury in 29 patients; postoperatively,
97% of the patients could achieve elbow
flexion. Novak and Mackinnon128 reported their results of terminal anterior interosseous nerve-to-deep motor branch of
the ulnar nerve transfer in the setting of
high ulnar palsy with mean follow-up of
18 months in 8 patients. All patients had
reinnervation of the ulnar nerve intrinsic
hand muscles, with improved pinch and
grip strength.
7. Kline DG. Nerve surgery as it is now and as
it may be. Neurosurgery. 2000; 46(6):12851293.
Conclusion
13. Isaacs JE, McDaniel CO, Owen JR, Wayne
JS. Comparative analysis of biomechanical
performance of available “nerve glues.” J
Hand Surg Am. 2008; 33(6):893-899.
This review summarized the current
concepts of peripheral nerve injury repair
and regeneration to inform physicians on
current and future perspectives unfolding in
the ever-growing field of nerve regeneration
research. It is evident that today’s advances
in translational research and biotechnology,
together with a greater understanding of the
mechanisms underlying the neurobiology
of nerve regeneration, can make yesterday’s
chimera tomorrow’s reality.
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