Abstract
Background: Tendon-repair techniques have evolved to increase the
construct strength of the repair site in order to permit early active range of
motion without tendon gap or rupture. The present study evaluated the
hypothesis that the injection of botulinum neurotoxin type-A (BoNT-A) into the
gastrocnemius muscle will reduce the active force production of that muscle
below the force required to rupture the associated, repaired Achilles
tendon.
Methods: Seventy-nine rat Achilles tendons were surgically bisected
and were repaired with use of a two-strand core suture with a running epitenon
repair. After the repair, the animals were treated with unilateral
intramuscular (gastrocnemius) injections of either BoNT-A (6 U/kg body weight)
(thirty-seven rats) or saline solution (forty-two rats). Operatively treated
ankles were fixed in the neutral position with a percutaneous pin for the
first two days after surgery. Unrestricted ankle motion and weight-bearing
were allowed after the second postoperative day. An assessment of gap
formation or rupture at the repair site, electrophysiologic measurements of
force applied to the tendon, and an assessment of the strength of the repaired
tendon were performed.
Results: Intramuscular BoNT-A injections produced a significant,
reversible reduction in active muscle force (p < 0.007). Twitch and tetanus
contractions decreased to approximately 25% of the values for the control side
within one week, remained at <50% of the values for the control side at one
month, and returned to normal levels by six months. The tetanic force
capability of the muscles that had been injected with BoNT-A was fivefold to
tenfold less than the force required to rupture the associated Achilles tendon
for as long as four weeks after tendon repair. The spontaneous Achilles tendon
rupture rate of repaired tendons in the BoNT-A group was three times lower
than that in the saline solution group at one week, and the tendon rupture
force was significantly higher in the BoNT-A group between one and three weeks
after repair (p < 0.007). There was no significant difference in tendon
rupture force between the two groups after three weeks.
Conclusions: Intramuscular gastrocnemius BoNT-A injections were
associated with a significant reduction in force-generating potential, such
that the muscle was incapable of actively producing enough force to rupture
the repaired Achilles tendon in this rat model of tendon repair.
Clinical Relevance: The temporary decrease of active muscle-tendon
forces produced by intramuscular BoNT-A injections has the potential to allow
early active motion, to provide a pharmacologically mediated aid
(bioprotection) to improve patient compliance with rehabilitation, and to
enhance patient outcomes.
Over the past twenty years, research on tendon-repair techniques has been
directed primarily at increasing the strength of the repair site in order to
prevent tendon gapping and/or rupture during
rehabilitation1-13.
Adhesions and/or ruptures that often occur with immobilization are
unacceptable postoperative complications. Force at the tendon-repair site is
generated by active muscle contraction, co-contraction of antagonist muscles,
and friction between the tendon and the surrounding tissues. The force that is
generated by a muscle depends on the muscle's resting length and is affected
by joint positioning. Following tendon repair, motion at the repair site is
essential to minimize adhesion
formation14,15.
However, unrestricted motion produces a tendon gap when the forces that are
generated at the repair site exceed the mechanical integrity of the
suture-tendon repair construct and the biologic capability of the repaired
tendon. In order to create a tenorrhaphy capable of immediate unrestricted
motion, newer and stronger sutures have been developed, specific
rehabilitation protocols have been
devised16,17,
and surgical devices have been designed to facilitate tendon
repair18. The
evolution of repair techniques has emphasized the development of methods to
maximize the strength and alignment of the repair core and epitendinous
construct, including the use of multiple (six or more) strands of suture and
larger core sutures (including steel intratendinous devices). These suture
techniques have been combined with complex splinting and rehabilitation
protocols in order to decrease or neutralize any muscle forces that might
disrupt the tendon-healing
process19,20.
To date, techniques to modify muscle force temporarily during
tendon-healing have not been explored. However, intramuscular injections of
botulinum neurotoxin A (BoNT-A) offer a way to chemically denervate muscles
associated with repaired tendons. BoNT-A blocks the release of acetylcholine
from presynaptic motor nerve
terminals21 and
induces reversible muscle
weakness22,23.
BoNT-A is widely used for adjunctive treatment of conditions characterized by
muscle overactivity, including strabismus, blepharospasm, spasmodic dysphonia,
hemifacial spasm, and spasmodic
torticollis24,25.
The efficacy and safety of BoNT-A in the treatment of spasticity has been
established in recent clinical
trials26-28.
In addition, BoNT-A, injected intramuscularly, predictably decreased muscle
force generation in the injected muscle of a
rat29. The toxin
weakened the target muscle by 75% three days after the injection, and the
muscle remained weakened after four
weeks29.
On the basis of these data, a rat tendon repair model was developed to
evaluate the temporary and controlled reduction of muscle force effected by
toxin injections to protect tendon repair site integrity, to permit safe
postoperative active and passive range of motion, and to reduce the prevalence
of postoperative complications. The concept of using intramuscular toxin
injections to produce partial selective muscle paralysis can be considered as
a form of bioprotection.
The hypothesis of the present study was that the injection of BoNT-A into
the gastrocnemius muscle will reduce the active force production of that
muscle below the force required to rupture the associated, repaired Achilles
tendon. The specific aim of the present study was to compare the
force-generating capacity of the gastrocnemius muscle following BoNT-A
injection (or saline solution injection) with the force required to rupture
the repaired Achilles tendon.
Seventy-nine Sprague Dawley rats (Harlan; Indianapolis, Indiana) that were
one month old were used in the study (Table
I). The protocol was approved by the institutional Animal Care and
Use Committee in accordance with National Institutes of Health and United
States Department of Agriculture guidelines for the care and use of laboratory
animals. Achilles tendon transection and repair were performed in two
experimental groups, with the tendon repair being followed immediately by
either botulinum toxin (BoNT-A) injections (thirty-seven rats) or saline
solution injections (forty-two rats) into the operatively treated hind limb.
The animals were housed in an Association for the Assessment and Accreditation
of Laboratory Animal Care-approved animal resources facility in a
temperature-controlled room (20°C to 22°C) on a twelve-hour light-dark
cycle and were provided with rat chow and water ad libitum. The rats were
evaluated in groups of five, six, or seven animals at either one, two, three,
four, eight, twelve, or twenty-four weeks after tendon repair
(Table I). At the end of the
experimental protocol, each rat was anesthetized and then was killed with
sodium pentobarbital (195 mgkg, administered intraperitoneally).
Surgical Technique
Following the induction of anesthesia with use of 1% isoflurane, the left
hind limb of each animal was shaved and prepared for aseptic surgery, and the
animal was transferred to the operating room. With use of aseptic technique, a
small longitudinal incision was made unilaterally on the posterior aspect of
the left hind limb. The Achilles tendon was exposed, incised at its midpoint,
and repaired under an operating microscope with use of a two-strand core
suture (5-0 polypropylene; Ethicon, Somerville, New Jersey) with a running
epitenon repair (7-0 polyprolene) (Fig.
1). The left hind limb gastrocnemius then was injected with equal
volumes of either BoNT-A or saline solution. All injections were made
unilaterally on the side of the tendon transection and repair (the left side).
The skin incision was closed with use of 5-0 Vicryl absorbable suture
(Ethicon). After skin closure, the ankle was stabilized with use of a
1.2-mm-diameter pin that was inserted percutaneously through the calcaneus,
talus, and tibial bone to provide temporary immobilization of the joint in a
neutral position during the first forty-eight hours after surgery. This
postoperative immobilization procedure was used after a pilot rat study
demonstrated that most repaired tendons ruptured if no immobilization was
provided during the first forty-eight hours after the repair procedure. The
pins were removed forty-eight hours after surgery. For animals in both
experimental groups, the right hind limb served as a nonoperatively treated
control limb.
Toxin and Saline Solution Injection Technique
The toxin was prepared for injection by adding 2 mL of physiological saline
solution to a 100-U vial of botulinum toxin type A (BOTOX; Allergan, Irvine,
California), with the final concentration being 50 U of toxin/mL of saline
solution. The amount of toxin injected was calculated on the basis of the
rat's body weight and a standard dosage of 6 U of toxin/kg body
weight30, an
accepted clinical dosage. A volume of 10 to 15 µL was injected unilaterally
under direct visualization of the muscle into the left gastrocnemius with a
Hamilton syringe (Fisher Scientific; Pittsburgh, Pennsylvania). Equal volumes
and units of toxin (5 to 7.5 µL) were injected into both the medial and
lateral aspects of the left gastrocnemius. Similarly, an equivalent volume of
saline solution was injected into the medial and lateral heads of the left
gastrocnemius in the rats in the saline solution group, which served as
operatively treated, injected controls.
Outcome Measures
Gross Observation of Tendon Repair Site
At each experimental time-interval, groups of five, six, or seven rats were
anesthetized, and an incision was made to expose the repair site of the
Achilles tendon. The continuity of the tendon and the formation of scar tissue
at the repair site were documented. Lack of continuity associated with tendon
stump retraction was defined as a total rupture, whereas partial continuity of
the tendon with disruption of part of the repaired epitenon was defined as a
partial rupture.
Muscle Force Generation
After gross observations were documented, muscle force generation was
measured in all rats as previously
described29,31.
The limb was immobilized with use of Kirschner wires that passed through the
ankle joint and the femur to fix the leg to a wooden table in order to prevent
gross motion of the joint and to isolate the motion of the repaired tendon.
The gastrocnemius muscle was left in situ until muscle force generation
studies were started. After the repaired tendon was exposed, the tendons
demonstrating gross rupture at the repair site were not studied further and
were recorded as having sustained a spontaneous complete rupture. In rats with
tendon continuity (including those with a partial rupture), the adhesions
surrounding the soft tissues were released, and, with use of a #15 scalpel
blade, the calcaneus was disarticulated from the surrounding tarsal bones with
the repaired tendon attached to it. The calcaneus and the attached distal part
of the tendon were tied with wire suture material at the tendon-calcaneus
junction. The suture was connected to a force transducer (model FT03; Grass
Technologies, West Warwick, Rhode Island). The transducer then was connected
to a force transducer amplifier (model 13-G4615-50; Gould, Cleveland, Ohio).
The combination of joint pinning and disarticulation of the calcaneus
established a linear relationship between the force transducer and the
insertion of the gastrocnemius muscle. The muscle was pretensioned to 10 g
prior to nerve stimulation.
Twitch was generated by stimulation of one motor unit, while tetanus was
generated by the summation of all motor units in order to produce supermaximal
stimulation32.
Tetanic contractions are considered to represent the maximal muscle force
generation capacity of the
muscle32. The
sciatic nerve in both groups was exposed and then was stimulated (SD9
stimulator; Grass) with increasing voltage to produce the maximum isometric
single twitch. The frequency of stimulation was increased with use of maximum
isometric twitch simulation parameters until the maximum tetanic contractile
force was generated. The responses were recorded with a calibrated recording
oscillograph (RS 3800; Gould) linked to the force transducer.
Tendon Strength
To determine the tendon strength following repair, the maximal mechanical
force (in Newtons) that was required to rupture the repaired tendon by means
of either tetanic contraction or manual distraction was measured with a force
transducer and was compared between the animals in the BoNT-A and saline
solution groups. If sciatic nerve tetanic stimulation was not sufficient to
produce tendon rupture, manual distraction was used to generate the force
necessary to produce tendon rupture.
Time-Course of Muscle Recovery
The time-course of muscular recovery following botulinum toxin injections
was studied by comparing the muscle force values for the repaired and injected
tendon (left hind limb) and the contralateral tendon (right hind limb) at
different time-points from two to twenty-four weeks after tendon repair. The
muscle force that was generated through the repaired tendon was expressed as a
percentage of the muscle force that was generated on the contralateral side,
and the percentages were compared between the BoNT-A group and the saline
solution group.
Statistical Analysis
Data on muscle force generation (twitch and tetanus contraction) were
normalized by expressing the data as a percentage of the values on the
contralateral (control) side. The normalized data and tendon strength in these
two groups were analyzed with use of an unpaired t test. The level of
significance was set at 0.007 on the basis of Bonferroni's method of multiple
comparisons.
Gross Observations
The protective effects of chemodenervation on the tendon repair site were
observed early after repair. One week after repair, one of six rats in the
BoNT-A group sustained a partial tendon rupture and none sustained a total
rupture (Table II). In
comparison, two of six rats in the saline solution control group sustained a
partial tendon rupture and two sustained a total rupture
(Table II). After one week, it
was not possible to reliably visually assess the degree of tendon rupture in
these animals because scar tissue and adhesions were evident in both groups
across the repair site. Three weeks after repair, the surfaces of the tendon
specimens in the BoNT-A group were smooth, with a glistening appearance
(Fig. 2). In contrast, in the
saline solution group, exposed core sutures and increased scar tissue (as
compared with that in the BoNT-A group) were observed across the repair site
(Fig. 2). Four weeks after
repair, increased scar tissue with heterotopic ossification across the repair
site was observed in most of the animals in the saline solution group.
Muscle-Force Generation After Tendon Repair with BoNT-A or Saline
Solution Injections
In the BoNT-A group, intramuscular injections resulted in a 75% decrease in
the force of twitch contractions compared with the values on the contralateral
control side at one week (Fig.
3-A) and a >50% decrease one month after tendon repair and
injection. In contrast, in the saline solution group, both twitch and tetanus
contractions were only 10% less than normal between one and three weeks
(Figs. 3-A and 3-B). In the
BoNT-A group, the force of twitch contractions on the treated side was >50%
lower than that on the contralateral control side at one month. At all
time-points prior to eight weeks, twitch contractions were significantly
decreased in the BoNT-A group as compared with the saline solution group (at
the Bonferroni-adjusted level of significance of p < 0.007). However,
twitch contractions approached normal levels by twentyfour weeks in both
groups.
Similar to the findings for twitch contractions, tetanic contractions in
the BoNT-A group decreased to 25% of the values on the control side at one
week after injection and remained <40% of the values on the control side at
each time-point during the first month
(Fig. 3-B). In the BoNT-A
group, tetanus returned to 76% of the baseline level at twelve weeks after
injection and returned to the normal level by twenty-four weeks
(Fig. 3-B). Muscle-force
generation produced by tetanic contraction, expressed as a percentage of
control (Fig. 3-B) or in
Newtons (Fig. 4), was
significantly attenuated in the BoNT-A group as compared with the saline
solution group (p < 0.007) during the first four weeks following tendon
repair.
Tendon Strength
All tendons in both groups, except for tendons with disrupted continuity,
were tested by neural stimulation, and if needed, by manual distraction in
order to measure the strength required to produce tendon rupture. One week
after tendon repair, none of the six tendons in the BoNT-A group ruptured
during any twitch or tetanus contraction measurement session
(Table II). Only four tendons
were tested at one week in the saline solution group because two tendons had
already sustained a total rupture. One (25%) of these four remaining tendons
ruptured during tetanus contraction.
The strength required to rupture the tendon, measured as force in Newtons,
was tested in both the BoNT-A group and the saline solution group. There was
no significant difference in tendon strength between the two groups from four
to twenty-four weeks after repair. However, from one to two weeks after tendon
repair, significantly more strength was required to rupture the tendons in the
BoNT-A group than in the saline solution group (p < 0.007)
(Fig. 4).
Relationship of Tendon Strength to Muscle Force Capability
Comparison of the maximum muscle force produced during tetanic contraction
revealed that the tetanic force in the BoNT-A group was consistently lower
than that in the saline solution group during the period from one to four
weeks after the tendon-repair surgery (Fig.
4). The force that was required to produce tendon rupture in both
the BoNT-A group and the saline solution group was significantly greater than
the tetanic force capability of the BoNT-A group during this time-period (p
< 0.007). These results indicated that the tetanic force produced by the
toxin-injected muscle would be insufficient to cause tendon rupture. Between
one and three weeks, there was no significant difference in the saline
solution group between the force that was required to rupture the tendon and
the tetanic force that was produced by the muscle.
Improvements in surgical technique, along with an increased understanding
of extensor and flexor tendon biomechanics, anatomy, and healing processes
have improved functional recovery following tendon injury and
repair33. However,
the return of digital function following tendon injury remains a
challenge19,34,
and controversy regarding the optimal tendon repair technique and
postoperative management protocol
persists34,35.
The challenge is to achieve tendon repair and healing while simultaneously
eliminating the formation of scar tissue and adhesions at the repair site that
limit tendon gliding after
healing20.
Possible Mechanism of Bioprotection
Pharmaceutical interventions that have been devised to facilitate
tendon-healing at the repair site after tendon repair include insulin-like
growth factor
(IGF-1)36, bone
morphogenetic protein-12
(BMP-12)37,38,
nonsteroidal anti-inflammatory agents
(NSAIDS)39,40,
and hyaluronic
acid41-45.
In contrast to those interventions, the BoNT-A injections that were used in
the present study may facilitate tendon-healing and repair by protecting the
tendon repair site from muscle contractile forces strong enough to cause
tendon rupture. The toxin dosage used in the present study to effect muscle
weakening follows the dosage guidelines used in clinical practice for various
disorders22,46.
Because the intramuscular injection of BoNT-A did not produce complete
paralysis or paresis, active as well as passive joint motion was maintained.
In contrast, cast immobilization does not prevent isotonic contraction and
therefore does not necessarily protect the tendon from stress produced by
muscle contraction.
Injection of BoNT-A into muscles may protect tendon repairs through a
variety of mechanisms. BoNT-A injections may reduce
pain47, thereby
facilitating rehabilitation and the associated active, protected early
processes of tendon-healing following tendon repair. BoNT-A injections
upregulate the expression of neuropeptides such as substance P and calcitonin
gene-related peptide
(CGRP)48-50;
these neuropeptides play substantial roles in the healing process following
Achilles tendon
rupture51,52.
BoNT-A could result in increased tendon strength through mechanisms
independent of muscle weakening; however, these mechanisms were not
investigated in the present study.
Unlike conventional treatments that involve the use of casting after
Achilles tendon rupture and repair, weakening of the gastrocnemius by means of
BoNT-A injection after surgical repair allowed early postoperative
mobilization, a factor that has been established to facilitate the
tendon-healing
process1,53-61.
Zlatkov concluded that patients benefit from an early active-motion
rehabilitation protocol following the operative treatment of extensor tendon
laceration55.
Gelberman and colleagues reported that the use of early, protected passive
mobilization is the most effective means of inhibiting adhesion formation
after tendon
repair54 and that
the duration of the daily controlled motion interval is a significant variable
influencing the return of flexor tendon function after
repair56. In the
present study, animals in both the BoNT-A group and the saline solution group
achieved early active and passive motion two days after tendon repair
following removal of the ankle pins at forty-eight hours. However, the muscles
that had been weakened by BoNT-A could not generate the active force necessary
to rupture the tendon, creating an environment similar to a regimen of
protected active and passive motion. In contrast, the muscles in the saline
solution group maintained their normal strength.
Potential Benefit of Bioprotection
Excessive isometric muscle contractions can occur even with a cast in
place. In our clinic during the past few years, two cases of tendon rupture
following tendon repair occurred in patients who had been managed with a cast.
In one case, a flexor tendon rupture resulted from a sudden muscle contraction
that occurred when the patient was greeting his friends at a party. In the
other case, an Achilles tendon rupture resulted from a sudden reflex-related
muscle contraction that occurred during a fall. In both cases, traditional
casting failed to prevent tendon rupture induced by excessive isometric muscle
contraction. Under such circumstances, bioprotection with use of BoNT-A could
play an important role in securing the repair site while achieving effective
active mobilization.
Recently, BoNT-A injections (at a dosage of 2.5 to 7 Ukg of body weight)
were used to weaken the forearm flexor muscles in young children who underwent
zone-II flexor tendon
repair62. In all
patients, tendon repair was associated with a good or excellent result
according to the Strickland criteria. In that study, BoNT-A injection-induced
muscle weakness resulted in a reduced need for stringent immobilization
protocols. No tendon ruptures were noted postoperatively.
Limitations
Data obtained from the present study, which involved a one-month-old rat
model, cannot be directly extrapolated to clinical cases because (1) the
structure of tendons in one-month-old rats changes during
maturation63-66,
(2) juvenile animals may respond to BoNT-A differently than adult animals do,
and (3) tendons in juvenile animals may heal differently after tendon repair
than tendons in adult animals
do65,66.
Additional studies involving mature rats must be performed before expanding
these studies in larger animal models. Eventual clinical trials of this
potential therapeutic application would depend on successful completion of
additional well-designed animal studies.
Because passive motion across the joint is retained even after botulinum
toxin-A injection, it is possible that the tendon was subjected to both
passive and active forces, resulting in a total tendon force exposure greater
than the active muscle force generation alone. However, because these
conditions were not tested in the current experiments, the magnitude of the
potential forces is unknown. The observation that no complete ruptures were
observed in the BoNT-A group suggests that the tendon repairs were not exposed
to forces greater than those required to produce complete rupture.
Clinical Relevance
It is unlikely that the potential clinical application of BoNT-A injection
will replace the postoperative placement of traditional casts. However, as a
complement to casting after tendon repair, bioprotection may provide several
benefits, including (1) decreased time of cast wear, (2) more effective joint
mobilization, allowing periodic removal of the cast without endangering the
tendon repair, (3) better functional outcomes, (4) protection of tendon repair
sites, and (5) prevention of unintended excessive muscle contractions, making
early mobilization safer.
Overview
In an animal model of tendon repair in which unrestricted ankle motion was
allowed two days after tendon repair, intramuscular injections of BoNT-A into
the rat gastrocnemius muscle were associated with a significant reduction in
muscle contractile capacity to levels significantly below those necessary to
rupture the associated, repaired Achilles tendon. These results support the
concept that temporary, controlled muscle weakness allows active and passive
range of motion without compromising tendon repair. The toxin-induced weakness
of the target muscle reduced the amount of force generated by the muscle
across the repair site. Therefore, the use of BoNT-A injections has the
potential to improve postoperative results without the addition of technically
demanding and/or expensive repair techniques and to decrease the likelihood of
patient noncompliance with rehabilitation protocols. ?
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