20
ORIGINAL ARTICLE
Therapeutic Effect of Passive Mobilization Exercise on
Improvement of Muscle Regeneration and Prevention of
Fibrosis After Laceration Injury of Rat
Ji Hye Hwang, MD, PhD, Yun-Ju Ra, MD, PhD, Kyung Mu Lee, MD, PhD, Ji Youl Lee, MD, PhD,
Sung Ho Ghil, PhD
ABSTRACT. Hwang JH, Ra Y-J, Lee KM, Lee JY, Ghil SH.
Therapeutic effect of passive mobilization exercise on im-
provement of muscle regeneration and prevention of fibrosis
after laceration injury of rat. Arch Phys Med Rehabil 2006;87:
20-6.
Objective: To evaluate the muscle healing effect of passive
mobilization exercises after a laceration injury.
Design: Randomized controlled trial.
Setting: Basic science laboratory.
Animals: Male Sprague-Dawley rats (N⫽36), age ranging
from 8 to 10 weeks and weight ranging from 300 to 400g.
Intervention: The bilateral gastrocnemius muscles were
lacerated. The left leg muscles were used as the study groups
and the right side was used as the control (lacerated muscles
without any treatment, n⫽8). In the exercise group (n⫽24),
passive mobilization exercise (15min/d) was performed for 5
days starting from different time points (2, 7, and 14d postlac-
eration). The decorin group (n⫽8) was injected with decorin
(50␮g at 14d postlaceration), which is a well-known antifi-
brotic agent. Four animals were used as the normal controls, in
which only the muscle strength was evaluated. All the animals
were killed 4 weeks after the laceration.
Main Outcome Measures: The histologic characterization
of muscle regeneration (hematoxylin and eosin staining, num-
ber and diameter of the centronucleated, regenerating myofi-
bers), muscle fibrosis (vimentin-positive area, Masson modi-
fied trichrome staining positive area), and muscle strength
(analysis of fast twitch strength).
Results: The level of fibrosis was more than 50% lower in
the exercise and decorin groups than in the control (P⬍.05).
The decorin group showed the highest number of regenerated,
new myofibers and the highest muscle strength. All of the
exercise groups, regardless of the starting time of exercise, also
showed significant improvement in regeneration and strength.
From the Department of Physical Medicine and Rehabilitation, Sungkyunkwan
University School of Medicine, Samsung Medical Center, Seoul (Hwang); Depart-
ment of Physical Medicine and Rehabilitation, Bobath Hospital, Seongnam,
Kyonggi-do (Ra); Department of Rehabilitation Medicine, College of Medicine,
Chungbuk National University, Cheongju, Chungbuk (KM Lee); Department of
Urology, Catholic University of Korea, College of Medicine, Holy Family Hospital,
Bucheon, Kyonggi-do (JY Lee); and Department of Biology, Kyonggi University,
Suwon, Kyonggi-do (Ghil), Republic of Korea.
Supported by the Samsung Biomedical Research Institute of Korea (grant no.
C-A4-339-1).
No commercial party having a direct financial interest in the results of the research
supporting this article has or will confer a benefit upon the authors or upon any
organization with which the authors are associated.
Reprint requests to Ji Hye Hwang, MD, PhD, Dept of Physical Medicine and
Rehabilitation, Sungkyunkwan University School of Medicine, Samsung Medical
Center, 50 Ilwon-dong, Kangnam-ku, 135-710 Seoul, Republic of Korea, e-mail:
hwanglee@smc.samsung.co.kr.
0003-9993/06/8701-9736$32.00/0
doi:10.1016/j.apmr.2005.08.002
Arch Phys Med Rehabil Vol 87, January 2006
However, the exercise group starting 14 days after the lacera-
tion showed the best results.
Conclusions: Stretching exercises after a muscle laceration
injury has a strong antifibrotic effect, as much as a well-known
antifibrotic agent, decorin. According to the results, the best
time to begin stretching exercises is 14 days after laceration for
antifibrosis and muscle regeneration.
Key Words: Exercise; Fibrosis; Muscle, skeletal; Regener-
ation; Rehabilitation; Wounds and injuries.
© 2006 by the American Congress of Rehabilitation Medi-
cine and the American Academy of Physical Medicine and
Rehabilitation
HERE ARE MANY TYPES of muscle injuries, including
T those that occur through direct trauma, such as laceration
and contusion, and those caused by indirect damage, such as
ischemia, denervation, and strain. However, in most cases, the
general processes of muscle damage and repair are similar.1-5
Traditionally the treatments have focused on conservative tech-
niques such as rest, ice, compression, and elevation (RICE),
heat, or immobilization; and other treatment options such as
continuous passive motion machines, and drugs.6 The optimal
treatment method for muscle injury has not been determined.1,5
The healing process of an injured muscle consists of 3
phases7: inflammation, repair, and remodeling. The inflamma-
tory phase is characterized by the formation of a hematoma,
muscle tissue necrosis, degeneration and the inflammatory cell
response. The repair phase includes the phagocytosis of the dam-
aged tissue, the regeneration of the striated muscle, the production
of connective tissue scarring, and capillary ingrowth. In the final
remodeling phase, the regenerated muscle matures and contracts,
and the scar tissue reorganizes. One way to accelerate muscle
regeneration is to increase the myogenic activity in the muscle
cells of an injured muscle. Recently, different biologic ap-
proaches have been used to enhance the level of muscle healing
after an injury, including the use of myoblast transplantation
and gene therapy based on the delivery of specific growth
factors.8,9 On the other hand, Järvinen and Sovari10 reported
that the excessive production of a connective tissue scar can
inhibit the complete regeneration of the muscle fiber, often
leading to incomplete functional recovery. Therefore, reducing
the fibrosis may be another way to enhance the healing after
muscle injury. It has been reported that the presence of trans-
forming growth factor ␤1 (TGF-␤1) at an injured site consti-
tutes the key event during the development of fibrosis, via the
activation of myofibroblasts.11 Decorin, a human proteoglycan,
is a well-known antifibrotic agent in various tissues, such as the
kidneys, liver, and lungs.12 It can bind to TGF-␤1 and neutral-
ize its biologic activity. A direct injection of human recombi-
nant decorin efficiently prevents fibrosis, enhances the level of
muscle regeneration in injured muscle, and more important,
can improve the recovery of strength in an injured muscle to a
level similar to that observed in a normal noninjured mus-
 PASSIVE MOBILIZATION EXERCISE AND MUSCLE REGENERATION, Hwang
cle.13,14 But these are nonphysiologic, invasive, and expensive
treatments.
It has been widely accepted that early mobilization or exer-
cise after a muscle injury promotes muscle healing. Järvinen7
reported that mobilization also induces faster and more inten-
sive capillary ingrowth from the cell borders of the injury
particularly in the early stages of healing. In contrast, Lehto
et al15 reported that the early mobilization induces the produc-
tion of granulation tissue with a parallel orientation but a poor
penetration of muscle fibers through the connective tissue scar.
However, the therapeutic effect of exercises of an injured
muscle on improving muscle regeneration and preventing fi-
brosis has not been determined.
We hypothesized that a mechanical stimulus such as passive
exercise, which enhances the proliferation and differentiation
of myoblasts in vivo, can also prevent the formation of scar
tissue. Our aims in this study were to evaluate the muscle
healing effect of passive stretching exercise at 3 different
starting times after a laceration injury, compared with the effect
of decorin on the healing of an injured muscle, and to establish
the best starting time of the exercise intervention.
METHODS
Experimental Animals
A total 36 male Sprague-Dawley rats (age range, 8⫺10wk;
weight, 300⫺400g) were used in these experiments. The ani-
mal research and care committee at the Samsung Biomedical
Research Institute of Korea approved all the experimental
protocols. A muscle laceration model was developed by lacer-
ating the gastrocnemius muscle of each leg based on previously
described studies.4,5,13,14 The rats were anesthetized by intra-
muscular injection of 0.3mL of ketamine (100mg/mL) and
0.2mL of xylazine (200mg/mL). The muscle was lacerated
with a surgical blade (#11) at the largest diameter, through the
lateral 50% of their width and 100% of their thickness. A
polydiaoxanon suture material (PDSII 5-0)a was placed at the
medial edge of the lacerated site, with 2mm of the suture
remaining visible on the medial edge of the lacerated site. After
the laceration, the hamstring muscle and skin were closed with
a black silk 4-0 suture,a and the animals were allowed to move
freely in small cages and received laboratory chow and water
ad libitum.
Procedure
The left gastrocnemius muscles were used as the interven-
tion group, and right gastrocnemius muscles were used as the
controls (laceration only without any treatment, n⫽8). We
divided the intervention group into 2 groups: group E (n⫽24;
the stretching exercise group) and group D (n⫽8; the decorin
injection group). Group E was classified according to the
treatment phase: the inflammatory phase (group E-2 [n⫽8];
beginning 2d after surgery), repair phase (group E-7 [n⫽8];
beginning 7d after surgery), and the remodeling phase (group
E-14 [n⫽8]; beginning 14d after surgery). Manual stretching
exercise was performed daily on group E for 5 days, 15
minutes per session, which consisted of 30° of dorsiflexion of
the ankle for 5 seconds followed by release and rest for 5
seconds. We used special positioning equipment made by us in
order to keep the positions of the left hip and knee immovable.
The decorin (n⫽8) injection was administered along the suture
material using a microsyringe.b Previous studies reported that a
decorin injection (50␮g) at 2 weeks after surgery had the best
healing effect.13,14 The left gastrocnemius muscles were in-
jected once with decorin (50␮g) at 14 days after laceration.
21
Four normal, nonlacerated muscles were evaluated by their
physiologic properties only. Thirty days after the laceration, the
animals were sacrificed to determine the level of improvement
in regeneration and the extent of fibrosis. The gastrocnemius
muscle was isolated and frozen in isopentane precooled in
liquid nitrogen. Histologic staining and physiologic analysis
was used to evaluate four muscles from each group. Serial 5␮m
sagittal sections were obtained for after surgery histologic
assessment.
Measurement Procedures
Muscle regeneration. The degree of muscle regeneration
was evaluated using hematoxylin and eosin (H&E) staining.
The number and diameter of the centronucleated, regenerating
myofibers were monitored within the injection, exercise sites,
as well as in the control group. In each sample, 8 random fields
within the injured area were selected. The measurements were
performed in a blinded manner in order to ensure the objectiv-
ity of the results. Low power (20⫻) and high power (40⫻)
images were obtained using a BX50 optical microscopec that
was connected to a spot image capture system DP 70 digital
camera.c The number and diameter of the centronucleated
myofibers were expressed as the number and diameter of
centronucleated myofibers per field and the diameter of the
myofibers.
Muscle fibrosis. Vimentin is expressed in macrophages,
capillary endothelia, and fibrocytes, and a high level is ex-
pressed within the scar tissue of an injured muscle.16 It is
expressed by myofiber early in development and shortly after
an injury. However, the mature myofibers and regenerating
myofibers present in an injured muscle 2 to 4 weeks after injury
do not express vimentin.2,3,5,13,16 Therefore, we used vimentin
as a marker for fibrosis. Cryosectioned muscles were used for
vimentin staining. The slides were blocked in 2% horse
serum for 1 hour, after washing the slides with antivimentin
conjugated Cy3d antibody for 1 hour at a dilution of 1:250.
The total vimentin-positive area was measured in 8 random
fields from each sample (n⫽4) of each group. The immu-
nofluorescence was then visualized using BX50 fluorescent
microscopy,c captured with a DP70 digital camera. The
image gauge, version 3.12,e was used to identify the vimentin
positive area, which is represented as a percentage.
We used Masson modified trichromef to compare the amount
of scar tissue development between the groups, as well as to
further confirm that the vimentin-positive area was a collage-
nous scar. The image was aggregated using the same tech-
niques used for vimentin. Olympus DP manager softwarec was
used to calculate the percentage area of fibrosis.
Contractile properties. Four muscles per group were ex-
amined to analyze the fast twitch strength. The rats were
anesthetized with 0.3mL of ketamine (100mg/mL) and 0.2mL
of xylazine (200mg/mL). Both gastrocnemius muscles were then
removed and mounted in a 5mL double jacketed organ bath at
36°C in Krebs solution (in mmol/L: NaCl⫽113, KCl⫽47,
CaCl2⫽1.2, MgSO4⫽1.2, NaHCO3⫽25, KH2PO4⫽1.2, glu-
cose⫽11.5), which was constantly bubbled with a 95% oxygen
and 5% carbon dioxide mixture. The initial tension was set at
20mN. The isometric contractions were measured using the
strain-gauge transducers coupled to a TBM4 strain gauge am-
plifierg and recorded on a computer using a data acquisition
program (WinDaq).h The sampling rate per channel was set to
500Hz. The amplitude of the stimulation-evoked contractions
was determined using a calculation program (WinDaq Ex).h
After 20 minutes equilibration, electric field stimuli were ap-
plied through 2 platinum wire electrodes positioned on the top
and bottom of the organ bath with a 4cm separation. The
Arch Phys Med Rehabil Vol 87, January 2006
22 PASSIVE MOBILIZATION EXERCISE AND MUSCLE REGENERATION, Hwang
muscle was stimulated with square-wave pulses of .25-ms
duration at the maximum voltage (100V). The first 1-Hz stim-
ulus was applied for 6 minutes and the number of muscle
twitches was recorded. The muscle was weighted after the test,
and the muscle strength was reported as millinewtons per gram.
Data Analysis
The average and standard deviation of the data were com-
pared using repeated-measures analysis of variance (ANOVA)
for statistical analysis (P⬍.05). SPSS, version 11.0,i for Win-
dows was used for statistical analysis.
RESULTS
Muscle Regeneration
The number of centronucleated, regenerating myofibers was
significantly higher in all interventional groups than in the
control muscle. Group D showed the highest number of regen-
erated new myofibers. Even though the number of new myo-
fibers was significantly lower than in the decorin treated group,
group E-14 showed a significantly higher number of new
myofibers than the other exercise groups.
Arch Phys Med Rehabil Vol 87, January 2006
Fig 1. (A) H&E stain sections
at 30 days after muscle lacer-
ation. (B) Number of centro-
nucleated, new generating
myofibers. (C) Diameter of
centronucleated, new gener-
ating myofibers. Abbrevia-
tions: C, control group; D,
group injected with decorin
(50␮g) at 14 days after muscle
laceration; E, group of stretch-
ing exercise started at 2 days
(E-2), 7 days (E-7), and 14 days
(E-14) after muscle laceration.
*ANOVA, P<.05.
The measurements of the regenerating myofiber diameter
indicated that only group E-14 achieved a statistically larger
diameter than the control group (fig 1).
Muscle Fibrosis
The level of fibrosis with vimentin and Masson trichrome
staining was decreased by more than 50% in the exercise
groups and decorin group compared with the control (P⬍.05).
Masson trichrome staining showed that the fibrotic area was
similar in the muscles treated with decorin and those given
stretching exercise (fig 2). However, vimentin staining indi-
cated that all interventional groups showed a significantly
lower level of fibrosis than control (P⬍.05) (fig 3).
Contractile Properties
The strength of the lacerated muscles was determined by
physiologic testing in order to evaluate the fast twitch strength.
The fast twitch strength of all the groups was compared. The
fast twitch in groups E-7 and E-14 was significantly improved,
compared with that of the control group. Group E-14 had a
slightly higher strength than group E-7, but there was no
statistical difference. The strength of the muscles in group D
was strongest among the intervention groups (fig 4).
 PASSIVE MOBILIZATION EXERCISE AND MUSCLE REGENERATION, Hwang
Fig 2. (A) Masson trichrome
staining. Collagenous area is
blue color. (B) Percentage of
collagenous area. Abbrevia-
tions: see figure 1. *ANOVA,
P<.05.
DISCUSSION
The management of a muscle injury varies, including RICE
immediately, additional physical therapies, and medications.
Surgical intervention might be necessary based on the type and
severity of the muscle injury. The treatment regimen has been
empirically adapted from clinical practice. These traditional
treatments usually do not promote a sufficiently rapid recovery
to satisfy the patients, and the recurrence of the injury is
common. This indicates that such treatments also fail to pro-
vide a full functional recovery and is likely to be ineffective in
preventing the formation of permanent scar tissue at an injured
site.3
Hurme et al17 described in greater detail the sequence of
changes at the ultra structural level, which occurs in the regen-
eration of muscle fibers after a contusion injury. Within 2 days,
the macrophages had already phagocytosed the necrotic muscle
fiber material. On day 3, satellite cells within the basal lamina
cylinders were activated into myoblasts. After 5 to 7 days, the
regenerating muscle cells extended out of the old basal lamina
cylinders into the central zone and began to pierce through the
scar. The scar tissue further condensed and the regenerating
23
myofibers had almost crossed the gap (day 14). On day 21, a
scar containing interlacing myofibers with little intervening
connective tissue had formed.
One way to get full recovery after muscle injury is to
enhance the regeneration of muscle cells. In muscle injuries,
the release of growth factors at the injured site is an important
step in initiating the healing process. These growth factors can
stimulate the growth and differentiation of various muscle-derived
cells.18 These growth factors are known to promote myoblast
proliferation and differentiation, which eventually leads to
muscle regeneration and healing after the injury,4,5 and are also
believed to be a key factor in the development of fibrosis in
various tissues.18,19 Kasemkijwattana et al20 reported that the
high level of muscle regeneration observed at 7 and 10 days
after the injury decreased over time until 35 days after the
injury. The development of scar tissue began 14 days after the
injury and gradually increased until 35 days.
It is likely that the development of the fibrosis is related to
the reduction of muscle regeneration, which was also observed
14 days after the injury. Therefore, another way to achieve the
acceleration of muscle regeneration is to reduce the fibrosis. Li
Arch Phys Med Rehabil Vol 87, January 2006
24 PASSIVE MOBILIZATION EXERCISE AND MUSCLE REGENERATION, Hwang
and Huard3 observed that TGF-␤1 was strongly expressed in
the injured skeletal muscle 3 days after injury. In addition, a
decrease in the expression level was observed 14 days after
injury. The in vitro results suggest that TGF-␤1 can induce the
expression of the myofibroblastic markers, such as ␣-smooth
muscle actin and vimentin, in muscle derived stem cells in a
dose-dependent manner. Therefore, TGF-␤1, which is the key
factor involved in the fibrosis of various tissues, also plays a
role in the development of scar tissue after muscle injury.
Accordingly, group D, which was treated with decorin, a
TGF-␤1 inhibitor, showed a significant reduction of fibrosis
and the highest number of regenerated myofibers and the
highest muscle strength. The increase in the regeneration of
muscle fibers possibly results from the reduction of fibrosis.
Fukushima et al13 reported that an injection of decorin at 2
weeks after the muscle laceration prevented the muscle fibrosis
and enhanced muscle regeneration. Sato et al14 reported that
further improvement in the healing of a muscle laceration is
Arch Phys Med Rehabil Vol 87, January 2006
Fig 3. (A) Vimentin immuno-
histochemical stain. (B) Per-
centage of vimentin positive
area. Abbreviations: see fig-
ure 1. *ANOVA, P<.05.
attained histologically by the combined administration of in-
sulin-like growth factor-1 to enhance the level of muscle re-
generation and decorin to reduce the formation of fibrosis.
However, the physiologic test revealed that the treatment with
decorin alone is the most effective method to restore the
physiologic strength of an injured muscle.
The development of biologic factors has important clinical
implications. However, many problems need to be solved be-
fore growth factor and growth factor inhibition therapy can be
used clinically. These include safety issues, the dosage, treat-
ment regimes, and effective delivery systems. Fukushima13
reported that an injection of decorin (50␮g) 2 weeks after the
muscle laceration had the best effect. A large amount of re-
combinant protein was required to efficiently improve the
healing of a very small mouse muscle. No data have been
generated from human trials. Dose finding and toxicity data are
not available. Early mobilization exercise or gentle stretching
exercise after a muscle injury has been widely used. Experi-
 PASSIVE MOBILIZATION EXERCISE AND MUSCLE REGENERATION, Hwang
Fig 4. The fast twitch strength of the lacerated muscle ex vivo.
Abbreviations: see figure 1; N, normal, nonlacerated muscle.
*ANOVA, P<.05.
mental results suggest that the exercise therapy induces more
rapid and intensive capillary ingrowth to the injured area,
as well as better muscle fiber regeneration and orientation.7,21
We chose to compare this with an antifibrotic agent.
In this study, we confirm previous reports13,14 that the level of
fibrosis is significantly lower, and the number of centronucle-
ated muscle fibers is significantly higher, in decorin-treated
groups. The stretching exercise, regardless of when initiated,
reduced the level of fibrosis as much as decorin. However, we
failed to find the optimal starting time of exercise after muscle
injury for antifibrosis. From the viewpoint of muscle regener-
ation, decorin was associated with the greatest number of new
myofibers and greatest twitch response, but not with increase in
myofiber diameter. However, decorin was significantly supe-
rior to exercise with respect to the number of new myofibers
and fast twitch strength. These findings may be physiologically
interdependent, although we did not specifically test for this.
It is believed that there are several mechanisms involved in
reducing the level of fibrosis of injured muscle that is treated
with stretching exercise. The mechanical load is now recog-
nized to be a powerful regulator of the cell phenotype, which
influences many cell functions such as the orientation, replica-
tion, growth factor production, and collagen synthesis.22 Fibro-
blasts are subjected to both active (contraction) and passive
tension (pulling from adjacent cells or the surrounding extra-
cellular mass).
In a previous study, fibroblasts grown in retracting collagen
lattices demonstrated increased collagen synthesis and lower
collagenase activity.23 First, the stretching exercise might re-
duce the passive tension, and thereby increase the collagenase
activity. Li and Huard3 reported that myogenic cells, including
the muscle-derived stem cells that are present at an injured site,
upon stimulation, can differentiate into fibrotic cells as a result
of the muscle injury. The loss of numerous regenerating myo-
fibers after a muscle injury suggests that not only might the
early myogenic precursors be triggered to differentiate into a
fibrotic lineage, but so might the differentiated muscle cells.
Second, the injured muscle treated with stretching exercise
might interrupt the early myogenic precursors and the differ-
entiated muscle cells could differentiate into a fibrotic lineage.
And third, stretching exercise regulated the biochemical medi-
ators such as TGF-1 and platelet-derived growth factor.
Muscle tension has been regarded as being essential for the
good orientation of the regenerating myofibers. Myofibroblasts
and the surrounding collagen fibers are also oriented parallel to
25
the direction of the contraction. It is possible that the contrac-
tion force of the myofibroblasts in the scar tissue is transmitted
to the myofibers, and is helpful in promoting their growth.17
The contraction of scar tissue brings the ruptured ends of the
muscle fibers closer together. This enables myotubes to cross
over the injured area and to repair the rupture. On the other
hand, the contraction of scar tissue makes the connective tissue
more compact. This makes the penetration of regenerating
muscle fibers through it more difficult. Therefore, in a recon-
structed muscle, there is an optimum ratio between the extra-
cellular matrix and the myofibers, which maximizes the phys-
iological strength.14,24 In this study, group D showed the
strongest fast twitch strength force, which was almost the normal
strength. The results showed that the fast twitch strength of group
E-14 was significantly stronger than the control group, but
weaker than group D. It is possible that healing muscle does
not have sufficient regeneration of myofibers for the optimum
ratio.
In the normal pathophysiologic process after a muscle in-
jury, the increase in fibrosis and the reduction of regeneration
are observed 14 days after the laceration. Therefore, the begin-
ning of stretching exercises 14 days after the muscle injury is
presumed to be appropriate for preventing fibrosis and improv-
ing the level of regeneration.
The optimal duration for a stretch or the total duration of
each exercise session is still a matter of controversy. In prac-
tice, for normal muscle it is enough to hold a stretch for 15 to
30 seconds and repeat it 3 to 5 times.25 We assumed that
lacerated muscle was more susceptible to microtrauma and that
the regeneration of muscle fiber would easily be interrupted.
So, we used 5 seconds for the duration of a stretch and 15
minutes for the total duration of each exercise session. We
observed that the injured leg of the experimental animal could
not be moved as much as the uninjured side. Therefore, the
addition of 15 minutes of passive stretching exercise to an
animal’s daily activity in a small cage should make a difference
to our results. Further studies of the effect of intensity, fre-
quency, and duration of the stretching exercises need to be
carried out, as well as the effect of combination therapy.
CONCLUSIONS
This study examined the muscle healing effect of gentle
passive stretching exercise after a laceration injury and estab-
lished a clinical treatment method. The results showed that
both stretching exercise and decorin improve muscle regener-
ation and prevent fibrosis after a muscle laceration. Even
though stretching exercises have a strong antifibrotic effect, as
much as the well-known antifibrotic agent decorin, they make less
improvement on the muscle regeneration. Within the exercise
groups, the best time to begin stretching exercise for antifibrosis
and muscle regeneration was 14 days after laceration.
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