Full text of DOI:10.1097/00005537-200205000-00022

The Laryngoscope
Lippincott Williams & Wilkins, Inc., Philadelphia
©
2002 The American Laryngological,
Rhinological and Otological Society, Inc.
End-to-Side Neurorrhaphy and Lateral
Axonal Sprouting in a Long Graft Rat Model
B. Goheen-Robillard, MD; T. M. Myckatyn, MD; S. E. Mackinnon, MD; D. A. Hunter, RT
Objective/Hypothesis: Controversy exists regard-
ing collateral axonal sprouting across an end-to-side
neurorrhaphy to provide functional motor reinnerva-
tion of a target organ without compromise of the do-
nor nerve. Rat models may be limited in the study of
end-to-side repair given potential contamination
from the proximal nerve stump of the recipient distal
nerve and the use of antagonistic muscle groups for
donor and recipient. The current study attempts to
address these issues by using a rat model in which an
end-to-side coaptation is performed with a long graft
interposed between the intact donor tibial nerve and
the divided, distal contralateral tibial nerve. Materi-
als and Methods: The graft used in proximal end-to-
side coaptation consisted of both sciatic nerves in a
donor syngeneic animal. The distal repair to the con-
tralateral tibial nerve was done immediately or in a
delayed fashion to allow potential motor axons to
transverse the graft before division of the recipient
tibial nerve. Results: After 24 weeks, axons were noted
to transverse the entire distance of the graft and into
the contralateral distal posterior tibial nerve. A sig-
nificant increase in axonal numbers was observed in
the immediate repairs compared with the delayed. No
animal recovered functional motor ability on the con-
tralateral side as assessed by walking tracks. Conclu-
sions: These findings suggest the importance of imme-
diate distal neurotrophic factors in encouraging
nerve regeneration even in a long graft end-to-side
repair. Our model is successful in demonstrating in-
nervation through an end-to-side coaptation but
questions its use given the lack of motor recovery. Key
Words: End-to-side neurorrhaphy, termino-lateral re-
pair, axonal sprouting.
denervation of distal motor targets often leads to irrevers-
ible muscle atrophy after such an injury, especially when
a primary repair of the injured nerve is not feasible. The
novel strategy of end-to-side repair in this scenario could
potentially provide a source of motor axons both close to
the recipient target muscle and without causing donor
deficit. End-to-side repairs have been conclusively shown
to facilitate sensory sprouting. If a motor axon is divided,
such as in partial hypoglossal to facial nerve transfers, the
proximal portion will regenerate through an end-to-side
nerve repair to innervate the new recipient target. What
remains controversial is whether motor axons from an
intact nerve will de novo sprout into an end-to-side neu-
rorrhaphy. In other words, does the transected distal end
of the recipient nerve stimulate collateral sprouting from
intact motor axons without donor disruption?
Criticism of end-to-side neurorrhaphy models in-
cludes the use of ipsilateral nerves for donor and recipient
that supply antagonistic muscle groups with little regard
for the subsequent disruption of spinal and cortical path-
1
ways (i.e., peroneal nerve vs. tibial nerve). Another con-
cern is that axons from the cut proximal stump of the
recipient nerve may inadvertently contaminate the re-
2
pair. Recent studies, primarily in the rat, looking at
end-to-side neurorrhaphy have rendered variable results
with little consistency in terms of surgical procedure, tech-
nique, or subsequent histologic, electrodiagnostic, or func-
tional assessment. Some investigators have suggested
that both motor and sensory collateral sprouting can occur
3
,4
with end-to-side repair
with subsequent physiological
5,6
recovery of previously denervated muscle and meaning-
3
Laryngoscope, 112:899–905, 2002
ful functional recovery. Conversely, others have shown
that predominantly sensory regeneration occurs in an
end-to-side neurorrhaphy, even at 4 to 6 months post-
procedure survival.
INTRODUCTION
Recovery of function following a nerve injury fre-
quently yields less than satisfactory results. Prolonged
7,8
The current study endeavors to address some of these
unresolved issues by coapting a nerve graft end-to-side to
an intact tibial nerve. The graft is brought across the
midline and anastomosed to the distal end of the con-
tralateral tibial nerve to attempt reinnervation of the
corresponding contralateral muscle group. This avoids the
use of antagonistic muscle groups necessary in other end-
to-side models. Functional recovery was based on regen-
eration from motor neurons originating in the contralat-
eral spinal column from the target muscle, which will help
From the Departments of Otolaryngology–Head and Neck Surgery
(
B.G.-R.) and Surgery, Division of Plastic Surgery (T.M.M., S.E.M., D.A.H.),
Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Supported by the Peripheral Nerve Research Fund of the Division of
Plastic Surgery, Washington University.
Editor’s Note: This Manuscript was accepted for publication January
6, 2002.
1
Send Correspondence to Susan E. Mackinnon, MD, Washington Uni-
versity, Division of Plastic Surgery, One Barnes Hospital Plaza, Suite 17242,
St. Louis, MO 63110, U.S.A. E-mail: mackinnons@msnotes.wustl.edu
Laryngoscope 112: May 2002
Goheen-Robillard et al.: End-to-Side Long Graft
899

to further delineate the use of end-to-side neurorrhaphy in
donor nerves not originating in the same dorsal root gan-
glion or motor neuron pool as the recipient.
in proximity to the contralateral tibial nerve. The contralateral
hind leg of animals from group 3 was re-explored after an 8-week
period, and the distal portion of the nerve graft was released from
the surrounding fibrous capsule. It was then sutured to the
transected distal end of the contralateral tibial nerve. Group 3
animals were not chosen until after the initial surgical procedure,
thus blinding the surgeon to animals that were to have a subse-
quent distal repair. Group 4 had the same distal repair performed
at the time of initial surgery. The proximal divided end of the
tibial nerve was similarly enclosed in silastic tubing to prevent
contamination.
MATERIALS AND METHODS
Experimental Design
Adult male Lewis rats (weighing 250–400 g) were housed in
a dedicated animal facility and received water and chow ad libi-
tum. Animal care complied with all institutional and National
Institutes of Health guidelines. Animals were divided into six
groups with 10 animals per group (Fig. 1). Group 1 had an
end-to-side neurorrhaphy performed between the left distal per-
oneal nerve and ipsilateral tibial nerve. In groups 2 to 4, a graft
from a syngeneic donor was used to create an end-to-side neuror-
rhaphy from the donor left tibial nerve to the recipient right tibial
nerve. The distal end of the nerve graft was not repaired but left
free in the right thigh. Group 3 animals underwent a second
staged procedure at 8 weeks in which the distal end of the graft
was sutured to the divided distal stump of the contralateral tibial
nerve. Group 4 animals had the repair to the contralateral distal
tibial nerve immediately performed at the initial procedure. An-
imals were weighed and walked before surgery and every 2 weeks
before being killed at 24 weeks. A final group of 20 animals were
included in group 1 and 3 but were killed after 2 weeks to assess
for signs of early Wallerian degeneration of the distal donor
nerve.
Walking Track Analysis
Walking track analysis was used to evaluate rate hind-
9
footprint patterns as previously described. Walking tracks were
performed before any intervention and every 2 weeks thereafter
until the animals were killed. The footprint length was hand-
measured on the left side to assess pre- and postoperative walking
tracks for any evidence of loss of function related to the donor nerve.
Walking track analysis was also performed on animals after the
graft was repaired to the contralateral tibial nerve. The investigator
performing the walking tracks was blinded from the animal groups
by an additional investigator (T.M.) who selected the animals with-
out identifying them to the first investigator (B.G.).
Histomorphometric Analysis
Donor left tibial nerve, including the end-to-side repair, the
recipient distal or graft nerve, and a portion of the contralateral
tibial nerve in groups 5 and 6, were obtained from the animals for
histologic examination. Immediately after harvest, nerves were
fixed and stored en bloc. Half of the nerves were fixed in a 3%
glutaraldehyde solution and washed in 0.1 mol/L phosphate
buffer (Fischer Scientific, Fair Lawn, NJ) and postfixed in 1%
buffered osmium tetroxide (Polysciences, Warrington, PA), rinsed
in 0.1 mol/L phosphate buffer, and dehydrated in a graded series
of ethanol solutions. Nerve segments were then infiltrated with a
graded Araldite-propylene oxide (Fischer Scientific) mixture and
embedded in Araldite 502 (Polysciences). Nerves were cut into
1-␮m cross sections using a LKB III Ultramicrotome (LKB
Produkter A.B., Broma, Sweden). Sections were stained using 1%
toluidine blue and visualized under light microscopy to assess
nerve architecture, extent of myelination and nerve innervation,
and the presence of Wallerian degeneration.
Surgical Procedure
Animals were anesthetized for surgery through a subcuta-
neous injection of 75 mg/kg ketamine (Fort Dodge Animal Health,
Fort Dodge, IA) and 1 mg/kg medetomidine hydrochloride (Pfizer
Animal Health, Exton, PA). A standard hind limb muscle split-
ting approach was used to expose the left sciatic and tibial nerves,
using a Wild M651 operating microscope to aid in identification
(
Leica Microsystems, Deerfield, IL). In group 1 animals, the per-
oneal nerve was transected 1 to 3 mm distal to the sciatic nerve
trifurcation. A 0.5-mm slit was made in the epineurium and
perineurium of the tibial nerve. The cut end of the distal peroneal
nerve was mobilized and coapted with four 10-0 microepineurial
sutures end-to-side to the slit in the tibial nerve. Care was taken
to enclose all proximal nerve stumps in silastic tubing to control
for contamination.
Groups 2 to 4 had similar exposure of their left tibial nerve.
A graft was prepared from a donor syngeneic animal at the same
time by harvesting both sciatic nerves. The nerves were joined
end to end to create the 8-cm graft. After creation of the perineu-
ral window in the donor tibial nerve, an end-to-side neurorrhaphy
was performed with the nerve graft. The graft was tunneled
subcutaneously across the back of the animal and allowed to rest
Microscopic images were studied using a digital image-
analysis system linked to morphometry software (Leco Instru-
ments, St. Joseph, MI) using a video monitor calibrated to 0.125
␮m/pixel. Cross sections throughout the grafts were assessed by
the computer for total fascicular area and total fiber numbers
through digitized information based on gray and white scales. Six
randomly selected fields per nerve (or a minimum of 500 myelin-
Fig. 1. Schematic diagram outlining the
surgical procedures performed within
each animal group.
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00

ated fibers) were evaluated under 1000ϫ magnification for axon
width, myelin width, and fiber diameter. These primary values
were used to calculate the total number of myelinated fibers,
percentage of neural tissue (100ϫ neural area/intrafascicular
area), and percentage of neural debris (100ϫ area of debris/
intrafascicular area). The investigator performing the analysis
(D.H.) was unaware of the group from which each nerve was
obtained while performing this analysis.
The remaining harvested nerves were embedded in paraffin
blocks and 4-␮m sections were taken longitudinally at the site of
repair. The sections were subsequently stained with neurofila-
ment protein antibody (Dako Corp., Carpinteria, CA) that was
conjugated using the AEC Chromagen stain (Dako Corp.) for
visualization under light microscopy.
Fast blue retrograde tracer (Sigma, St. Louis, MO) was used
on two animals from group 4 at 24 weeks survival time to assess
origin of axons within the spinal cord. Injections were performed
with a microglass pipette into the graft distal to the repair site.
After 4 days, the animals were deeply anesthetized and transcar-
dially perfused with 100 mL of 0.9% saline, followed by 500 mL of
4% paraformaldehyde/0.25% glutaraldehyde in 0.1 mol/L sodium
acetate buffer (pH 6.5), followed by 4% paraformaldehyde in 0.1
mol/L sodium borate buffer (ph 9.5), and then 10% sucrose in 0.1
mol/L Sorenson’s phosphate buffer. The spinal cords were care-
fully removed at levels L4 to L5. Longitudinal serial frozen sec-
tions (15 ␮m) were cut with a cryostat and mounted on slides.
Epifluorescence microscopy with an ultraviolet filter was used to
examine sections for labeled motoneurons.
RESULTS
Histologic examination of the distal donor tibial
nerve beyond the end-to-side repair showed mild evidence
of Wallerian degeneration involving from 5% to 20% of the
nerve in the 2-week survival groups (Fig. 2). These ani-
mals showed some degenerating fibers proximal to the site
of repair as well. In the 2-week groups, the recipient nerve
or graft showed extensive Wallerian degeneration on ex-
amination without evidence of ingrowth of axons.
Fig. 2. Light micrographs demonstrating evidence of Wallerian
degeneration in distal donor tibial nerve at 2 weeks post-procedure.
Animals in the 24-week survival groups showed no
evidence of donor axonal degeneration proximal or distal
to the neurorrhaphy (Fig. 3). Group 1 showed abundant
axonal growth across the end-to-side repair between the
tibial and the distal peroneal nerve (Fig. 3). The number of
fibers in cross sections averaged 2630 Ϯ 502 (Fig. 4).
There was a normal distribution of smaller than average
nerve fibers without evidence of Wallerian degeneration
up to 2 cm distal to the end-to-side repair. Walking tracks
of group 1 showed a footdrop on the operated side, as
would be expected after division of the peroneal nerve.
This group showed the most evidence of regeneration into
the donor of the experimental groups, as evidenced by the
greatest width and density of fibers, as well as having the
largest percentage of nerve fibers within the nerve.
Group 2 with a graft but no distal repair also showed
minimal evidence of damage to the donor tibial nerve,
with a mild amount of distal donor nerve Wallerian de-
generation, as well as no difference in tibial walking track
function pre- and post-procedure. There was regeneration
noted across the end-to-side neurorrhaphy into the graft
(
A) Low-power micrograph showing focal degeneration within the
donor nerve. (Toluidine blue stain; x53). (B) Higher-power magnifi-
cation demonstrating clear demarcation between normal nerve ar-
chitecture and focal injury (Toluidine blue stain; x537).
evidence of ischemia and edema throughout, with the
layers of the perineurium markedly thickened, and in-
creased collagen and fibroblast infiltration between the
perineurial cells. The endothelium of the vessels within
the graft was markedly thickened. There was a gradual
decline of the number of fibers noted within the graft
progressing from proximal to distal from the repair site
(Fig. 5).
Group 3 animals with the delayed repair also dis-
played intact functioning of the donor tibial nerve after
graft placement, as demonstrated by consistent walking
tracks. On re-exploration of the contralateral hind leg, the
distal end of the graft was encased in dense scar tissue
from which it had to be mobilized. Axons were again noted
on neurofilament staining to traverse the entire length of
the graft, but were fewer in number than group 1. These
grafts contained 1326 Ϯ 892 fibers, similar to that ob-
served within group 2 (Fig. 4). There was also histologic
evidence of ischemic damage, with edema of the peri-
(
1300 Ϯ 993 fibers) (Fig. 4). On neurofilament staining of
sections, regeneration was noted to occur across the entire
graft, but with decreasing density of fibers in the more
distal portions of the graft. Histologically, the graft had
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901

Fig. 3. Photomicrograph illustrating do-
nor tibial nerve and recipient distal per-
oneal nerve in group 1 at 24 weeks. (A)
Proximal donor nerve demonstrating ab-
sence of Wallerian degeneration. (B) Dis-
tal donor nerve in which a number of
axons show decreased diameter, indi-
cating regeneration secondary to axonal
injury at the time of repair. (C) Distal per-
oneal nerve showing extensive regener-
ation across the repair site and into the
nerve (Toluidine blue stain; x537).
neurium and a small number of blood vessels within the
graft (Fig. 5). Walking tracks on these animals after con-
tralateral division of the tibial showed the expected
lengthening of the print length resulting from loss of gas-
walking tracks showed initial elongation of the contralat-
eral print. Despite the large number of nerve fibers, the
prints remained elongated and at no point showed short-
ening, which would indicate return of contralateral gas-
trocnemius function.
9
trocnemius function. No animal showed any subsequent
significant change in walking tracks at any survival point.
Group 4 animals with immediate end-to-end repair of
the graft to the contralateral tibial nerve also showed
minimal evidence of Wallerian degeneration of the distal
donor axons. Histologic examination of these grafts dem-
onstrated a significant number of regenerating axons
There was significantly less edema of the peri-
neurium in the group 4 grafts when compared with groups
without or delayed distal repair. A greater number of
blood vessels were also noted between the fascicles, sug-
gesting increased angiogenesis. There was also less colla-
gen and fibroblast infiltrate within the graft, correlating
with the increased fiber density (Fig. 5). Neurofilament
staining of these nerves demonstrated axonal growth orig-
inating from the donor tibial nerve across the full length of
the graft and entering into the distal contralateral tibial
nerve (Fig. 6). Retrograde labeling performed on two ani-
(
6507 Ϯ 2983) along the length of the graft and across the
end-to-end repair into the contralateral tibial nerve. This
group had increased fiber density when compared with
the other graft groups and was equal to group 1. The fiber
width was similar to that of groups 2 and 3 (Fig. 4). The
Fig. 4. Histomorphometry data demon-
strating a comparison of number of
nerve fibers, percent nerve within the
perineural sheath, density of fibers, and
width of fibers between the different
groups.
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02

Fig. 5. Photomicrograph showing prox-
imal and distal grafts in groups 2, 3 and
4
. (A and B) Group 2. Evidence of isch-
emia demonstrated by perineurial thick-
ening and collagen infiltration of graft.
Note even fewer fibers in the distal graft
as compared with the proximal graft,
along with continued signs of injury. (C
and D) Group 3. Ischemic damage is
evident in the graft, with thickened en-
dothelial lining of the blood vessels and
fibroblast infiltration. (E and F) Group 4.
Proximal and distal graft demonstrates
increased axonal fibers as compared
with groups 2 and 3. There is decreased
evidence of ischemia and collagen in the
graft (Toluidine blue stain; x537).
mals from group 4 demonstrated scattered, sparse motor
neuron labeling of the ipsilateral spinal cord at the L4 to
L5 level. Four motoneurons were identified in the first
animal, and five motoneurons were labeled in the second.
There was no staining observed within the contralateral
cord at this level.
may account for the inconsistency of findings within var-
ious experimental models of end-to-side neurorrhaphy.
Like in other studies of end-to-side repairs, the cur-
rent model demonstrates that regeneration of axons
across the repair occurs with minimal deficits to the donor
nerve. Creation of a perineural window in the donor nerve
did cause some mild axonal injury in our study, as evi-
DISCUSSION
In 1903, Ballance first reported using end-to-side
neurorrhaphy for reconstruction of the facial nerve dam-
10
aged by ear disease. The technique fell into disuse be-
cause of conflicting and disappointing results following
this report. Interest in this repair technique was renewed
by the use in rat models and facial palsy patients by
Viterbo and colleagues in 1992 with reports of good pre-
3
liminary results. However, end-to-side neurorrhaphy re-
mains controversial because of inconsistent findings with
regard to motor innervation. Given the variability of find-
ings in the current studies, it is imperative to continue to
address the question of functional motor recovery after
such a repair.
Recovery of peripheral nerves after injury is the cul-
mination of a series of complicated molecular, cellular,
biochemical, and electrophysiological mechanisms. These
occur at multiple levels within both the peripheral and
Fig. 6. Light micrograph of neurofilament staining in a graft from
group 4 at the site of repair. Fibers entering the graft from the donor
nerve are observed (x134).
11
central nervous system. The complexity of this process
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Goheen-Robillard et al.: End-to-Side Long Graft
903

denced by the observed Wallerian degeneration. However,
walking track analysis failed to demonstrate any evidence
of functional impairment to the donor nerve. Walking
track analysis may not be sensitive enough to detect sub-
tle changes in motor function, but this does suggest that
the level of injury did not significantly impact on the
performance of the donor muscle group. Prior studies have
suggested an intact epineurium and perineurium acts as a
Although the graft underwent degeneration as well, our
findings demonstrated that the immediate neurorrhaphy
of the graft to a distal nerve provided a dramatic improve-
ment in axonal growth when compared with the grafts
with delayed or no distal contact.
This would indicate that the delay in repair of the
distal end of a graft after end-to-side neurorrhaphy is
more deleterious to the growth of axons across the graft
than is benefited by attempting late repair to avoid muscle
atrophy. Not all muscle systems undergo atrophy after
denervation, which is thought to be secondary to the effect
of accessory neuronal input such as the autonomic system.
Further studies will be important to understand the
mechanism behind these findings of increased regenera-
tion with the use of an immediate distal target in the
end-to-side graft repairs.
Our model expands the study of nerve regeneration
after an end-to-side repair by designing an animal model
that may be more clinically applicable, given the distance
that nerves typically need to regenerate after damage
within humans. A graft allows the use of contralateral
donor and recipient nerves, decreasing the possibility of
collateral contamination and allowing synergistic muscle
groups to be studied. The ability of axons to regenerate
through a graft from the side of an intact tibial nerve to
the contralateral distal tibial nerve stump demonstrates
the potential for collateral sprouting axons to traverse
long distances. However, further investigation of end-to-
side neurorrhaphy is warranted given the findings of this
study before widespread clinical use.
4,12–14
barrier to collateral sprouting,
but the process of
removal may create axonal injury that accounts for at
least a portion of the collateral sprouting at an end-to-side
repair. Other end-to-side models have also demonstrated
degenerating axons within the donor nerve after re-
4,15
pair,
but the literature is conflicting regarding the
amount and impact of axonal injury occurring with end-
to-side repair. This study again questions whether lateral
sprouting occurs from intact donor axons or only after
injury to these axons and will need to be addressed in
further studies.
Another matter complicating our model and proposed
clinical uses of end-to-side repair is the atrophy of the
target muscle during the time interval it takes for regen-
eration to occur. Most models examine regeneration over a
short distance in which prompt innervation of the muscle
3,5,6,8
occurs.
However, in many clinical applications for
peripheral nerve injury, loss of muscle fibers before inner-
vation is a concern. The animals in our study did not
regain functional use of the contralateral gastrocnemius
muscle despite the demonstration of axonal growth
through the graft and into the distal tibial stump at pro-
longed survival times. Whether this was the result of lack
of motor axons within the graft, inability of central path-
ways to elicit a response in contralateral muscle groups,
need for even greater regenerative times, or an irrevers-
ible atrophy of the target muscle itself is not clear and will
need to be examined in future studies.
We designed our model to prejudice in favor of dem-
onstrating motor recovery. The group in which the distal
repair was delayed was intended to minimize the duration
of denervation of the target muscles. This was to increase
the likelihood of any motor axons present in the graft to be
able to reinnervate these muscles before irreversible atro-
phy. Similarly, if there was contamination from the prox-
imal tibial nerve on the contralateral side it should result
in functional tibial recovery. Even with these maneuvers,
no recovery was seen with walking track analysis. Also,
examination of the origin of axons within the graft using
retrograde tracing methods demonstrated few motor cell
bodies, suggesting primarily sensory axons available to
innervate the distal target. Perhaps our method of detect-
ing motor reinnervation was not sensitive enough to ob-
serve a positive recovery, but these findings do question if
end-to-side repair can provide enough motor axons to have
clinical use.
BIBLIOGRAPHY
1
. Lutz B, Chuang C, Hsu J, Ma S, Wei F. Selection of donor
nerves—an important factor in end-to-side neurorrhaphy.
Br J Plast Surg 2000;53:149–154.
. McCallister WV, Tang P, Trumble TE. Is end-to-side neuror-
rhaphy effective? A study of axonal sprouting stimulated
from intact nerves. J Reconstr Microsurg 2001;15:
598–604.
2
3. Viterbo F, Trindade JC, Hoshino K, Mazzon A. Two end-to-
side neurorrhaphies and nerve graft with removal of the
epineural sheath: experimental study in rats. Br J Plast
Surg 1994;47:75–80.
4
. Lundborg G, Zhao Q, Kanje M, Danielsen N, Kerns J. Can
sensory and motor collateral sprouting be induced from
intact peripheral nerve by end-to-side anastomosis?
J Hand Surg 2001;19B:277–282.
5. Tham S, Morrison W. Motor Collateral sprouting through an
end-to-side nerve repair. J Hand Surg 1998;23A:844–851.
6. Kalliainen L, Cederna P, Kuzona W. Mechanical function of
muscle reinnervated by end-to-side neurorrhaphy. Plast
Reconstr Surg 1999;103:1919–1927.
7
. Tarasidis G, Watanabe O, Mackinnon S, Stausberg S,
Haughey B, Hunter D. End-to-side neurorrhaphy resulting
in limited sensory axonal regeneration in a rat model. Ann
Otol Rhinol Laryngol 1997;106:506–512.
. Tarasidis G, Watanabe O, Mackinnon S, Stausberg S,
Haughey B, Hunter D. End-to-side neurorrhaphy: a long-
term study of neural regeneration in a rat model. Otolar-
yngol Head Neck Surg 1998;119:337–341.
8
The increased regeneration noted with immediate
distal repair also suggests that the presence of a distal
target is important in encouraging axonal growth from the
onset of repair, even when a significant distance separates
the donor and recipient nerves. Neuronal growth is en-
hanced by neurotrophic factors emanating from the de-
9. Hare G, Evans P, Mackinnon S. Walking-track analysis: a
long-term assessment of peripheral nerve recovery. Plast
Reconstr Surg 1992;89:251–258.
1
0. Ballance C, Ballance H, Stewart P. Remarks on the operative
treatment of chronic facial palsy of peripheral origin. BMJ
1903;2:1009–1013.
16
generating distal nerve stump in all types of repairs.
11. Lundborg G, Dahlin L, Danielsen N, Zhao Q. Trophism, tro-
Laryngoscope 112: May 2002
Goheen-Robillard et al.: End-to-Side Long Graft
9
04

pism, and specificity in nerve regeneration. J Reconstr
Microsurg 1994;10:345–354.
14. Al-Qattan MM, Al-Thumyan A. Variables affecting axonal
regeneration following end-to-side neurorrhaphy. Br J
Plast Surg 1998;51:238–242.
15. Giovanoli P, Koller R, Meuli-Simmens C, et al. Functional
and morphometric evaluation of end-to-side neurorrhaphy
for muscle reinnervation. Plast Reconstr Surg 2000;106:
383–392.
16. Seckel B, Ryan S, Gagne R, Chiu T, Watkins E. Target
specific nerve regeneration through a nerve guide in the
rat. Plast Reconstr Surg 1986;78:793–798.
1
1
2. Bertelli J, Soares dos Santos A, Calixto J. Is axonal sprout-
ing able to transverse the conjunctival layers of the periph-
eral nerve? A behavioral, motor, and sensory study of end-to-
side nerve anastomosis. J Reconstr Microsurg 1996;12:
559–563.
3. Okajima S, Terzis J. Ultrastructure of early axonal regener-
ation in an end-to-side neurorrhaphy model. J Reconstr
Microsurg 2000;16:313–326.
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