2020, Volume 36, Number 1, Page(s) 039-047
The Effects of Corticosteroid Injection in the Healthy and Damaged Achilles Tendon Model: Histopathological and Biomechanical Experimental Study in Rats
İlyas ARSLAN1, Istemi YÜCEL1, Turhan Beyza ÖZTÜRK2, Nazım KARAHAN1, M. Müfit ORAK3, Ahmet MIDI4
1Department of Orthopedics and Traumatology, Fatih Sultan Mehmet Training and Research Hospital, İSTANBUL, TURKEY
2Department of 2nd Grade Student, İstanbul Bahçeşehir University Faculty of Medicine, İSTANBUL, TURKEY
3Department of Orthopedics and Traumatology, İstanbul Bahçeşehir University Faculty of Medicine, İSTANBUL, TURKEY
4Department of Pathology, İstanbul Bahçeşehir University Faculty of Medicine, İSTANBUL, TURKEY
Keywords: Corticosteroid, Achilles tendon, Rats
To show the effects of corticosteroids on inflammatory reactions in the injured Achilles tendon in rats.
Material and Method: Thirty-two adult Wistar Albino rats were used in the study. The rats were divided into 4 groups. In the first group (Intact
Saline), saline solution was injected to the intact Achilles tendon. In the second group (Intact Corticosteroid), corticosteroid was injected to
the intact tendon. In the third group (Injured Saline), saline solution was injected to the injured Achilles tendon. In the fourth group (Injured
Corticosteroid), corticosteroid was injected to the injured tendon. All groups were sacrificed on day 30 and Achilles tendons were taken and
prepared for histological and biomechanical evaluation.
Results: According to the biomechanical test; mean load-to-failure of the Intact Saline group was significantly lower than the Intact Corticosteroid
(p=0.016), Injured Saline (p=0.001) and Injured Corticosteroid) (p=0.012) groups. According to the histopathological evaluation, tenocyte
mean of the Intact Saline group was statistically lower than the Injured Saline and Injured Corticosteroid groups. Tenocyte mean of the Intact
Corticosteroid group was statistically significantly lower than the Injured Saline and Injured Corticosteroid groups. The ground substance
mean of the Intact Saline group was significantly lower than the Injured Saline and Injured Corticosteroid groups. The ground substance mean
of the Intact Corticosteroid group was significantly lower than the Injured Saline and Injured Corticosteroid groups. There was no statistically
significant difference between the groups in terms of calcification.
Conclusion: It has been found that there is biomechanical and histopathological significant benefit of intra-tendon corticosteroid administration
in the experimentally generated Achilles tendon injury model.
Achilles tendon is one of the largest, strongest tendons
in the body and is the most common tendon that shows
pathological situations. Tendinopathies are confronted
within a wide range of clinical spectrum, and clinical
differentiation between lesions can be challenging for the
physician. It is likely that the tendons have pathological
changes before rupture and these changes also affect the
subsequent healing period. Individuals are often unaware
of these pathological changes that do not lead to symptoms
and develop achillodynia or tendon ruptures with minimal
Because the Achilles tendon faces higher in vivo stresses
than the other tendons, it is the most commonly traumatized
and most often ruptured tendon in the human body 1,2.
Achilles tendon ruptures are very common especially in sports activities where sudden load is applied to the tendon
and then abruptly abolish 2-4.
Tendon ruptures usually occur between the ages of 31-
49 and are more frequent in males 1,5. The etiology
is not fully understood, but the most common cause is
degenerative tendinopathy 1,2,6-8.
There are studies showing that steroid use or direct
injection into the tendon region increases the risk 9. In
an immobilized tendon, there is a microscopical decrease
in cellularity, collagen fibril diameter, collagen cross-links
and the entire collagen organization. At the same time, the
proteoglycan and water content may also change. Factors
affecting tendon healing include age, sex, hormonal status,
systemic disease presence, chronic drug use (especially
corticosteroid), size of the injured area, crushing injuries
that disturb the blood supply of tendon and surrounding
tissues, and the applied treatment methods.
The use of corticosteroids in Achilles tendinopathy is
still controversial 6-8,10-12. Corticosteroids affect the
healing in a negative way by suppressing the inflammatory
response, tenocyte proliferation and collagen synthesis.
They can cause spontaneous rupture by reducing the
tensile strength of the healing tendon 13. According to
some studies, corticosteroids delay tendon healing, cause
degeneration and impair biomechanical properties 14-21. However, there are also publications reporting no side
effects on the tendon and no increase the rate of Achilles
tendon rupture 22. There is no clear consensus on the
benefits and damages.
Our aim was to show the effect of the anti-inflammatory
activity of corticosteroids on the healing of Achilles tendon
damage by creating a damaged Achilles tendon model and
comparing the biomechanical and histological changes that
occur with the changes in the intact Achilles tendon.
Our study was carried out with approval from the Local
Ethics Board (approval no: 2016-16). In the study,
5-7-month-old rats weighing 300-350 grams were used.
Thirty-two Achilles tendons of 32 Wistar white female rats
with normal activity were included in the study. The rats were
housed with 3-4 rats in each cage during the experiment,
fed with standard laboratory nutrients. There was no liquid
and nutrient restrictions and the rats were divided into
4 groups with each group including 8 animals. The right
Achilles tendon was used as the experimental group, while
one left Achilles tendon was used as the control group in
each group. In the first group (Intact Saline), saline solution
was injected to the intact Achilles tendon. In the second
group (Intact Corticosteroid), corticosteroid was injected
to the intact tendon. In the third group (Injured Saline),
saline solution was injected to the injured Achilles tendon.
In the fourth group (Injured Corticosteroid), corticosteroid
was injected to the injured tendon. Trametasone sodium
phosphate (Diprospan, Eczacıbaşı, Turkey) was used for
corticosteroid injection. The dose was determined as 0.1 ml
(0.7 mg) 26
. Rats were maintained in standard laboratory
conditions (12 hours day time - 12 hours night time
lighting, 20-22 °C room temperature, 50-60% humidity) for
a week before starting work, and they were provided with
water and food as needed.
Preparation of Animals
Rats were anesthetized with an injection of 10 mg/kg
Rompun (Xylazine, Bayer, Germany) and 100 mg/kg
Ketamine HCl (Ketalar, Pfizer, USA) before surgery. Each
rats right leg was cleaned from hair with a razor blade. The right hind legs were sterilized by providing antisepsis
with a solution of 10% Povidone Iodine (Batticon, Adeka
Pharmaceutical, Turkey). 10 mg/kg Cefazolin Na (Cefazol,
Mustafa Nevzat, Turkey) was intramuscularly injected as a
preoperative antibiotic prophylaxis.
A separate surgical instrument was prepared for each
experimental animal in a sterile drape, and the rats Achilles
tendon was cut longitudinally on the skin starting from the
calcaneal insertion site and 5 mm lateral to the tendon.
(Figure 1A). The paratnon and tendon were exposed
(Figure 1B). The tendon damage model of these animals
was based on the Achilles tendon damage model proposed
by Akamatsu et al. 26.
Click Here to Zoom
|Figure 1: A) Skin incision. B) Exposure of tendon. C) Tendon damage. D) Tendon injection (damaged tendon). E) Skin closure.
F) Tendon injection (intact tendon).
According to this article, the tendon was discarded, and the
lateral incision made perpendicular to the fibers with a 15
mm lancet at 2.5 mm from the Achilles insertion (Figure
1C). 0.1 mL (0.7 mg) of betamethasone sodium phosphate
(Diprospan, Eczacıbaşı, Turkey) was intrathecal injected to
the site where the tendon rupture was made (Figure 1D).
The skin incision was closed with silk suture No. 4, and it
was not dressed (Figure 1E). For groups without Achilles
tendon damage model, the injection was performed by
exposing tendons with a smaller incision (Figure 1F).
At the end of the process, rats were released into cages
and free access to food and water was provided at room
temperature. At the end of 30 days, the experiment was
terminated by the sacrificing of the subjects. The right
Achilles tendon was subcutaneously skinned 2 cm proximal
to the insides, and the tendon was removed by opening the
paratenon (Figure 2A). To ensure that the Achilles tendon
was completely removed, the entire Achilles tendon was
excised with a piece of muscle from the triceps surae with a
3 mm bone piece cut from the calcaneus.
Click Here to Zoom
|Figure 2: A) Exposure
of tendon, calcaneus and
gastrocnemius. B) MTS
858 Mini Bionix II.
C) Tightening aluminum
plates. D) Anti-slip
Until biomechanical testing, samples were stored at -20 °C.
Biomechanical tests were carried out at Istanbul Technical
University Laboratory. Room temperature and humidity
were set to 20 °C ± 1 and 40% respectively. Fresh frozen
samples were dissolved at room temperature and saline was
used to keep them moist. For biomechanical testing, MTS
858 Mini Bionix II (MTS Systems Corporation, USA, 2014)
was used (Figure 2B).
Aluminum plate specially designed to hold the calcaneus,
gastrocnemius and tendon-containing tissues (Figure 2C)
and abrasive paper (Figure 2D) were used.
The system was set to 250 N with a displacement rate of
5 mm / min. Force was applied to the tendon until it splits.
The biomechanical evaluation was performed according
to the parameters of maximum load, maximum point
elongation and stiffness for each group. The average of each
group was taken and recorded.
The right Achilles tendon taken from each subject was kept
in neutral formaldehyde solution and sent to the Pathology
Laboratory. After 48 hours, the samples were placed into
decalcified solution for 15 days. After these procedures,
the tendons were cut longitudinally and embedded in
paraffin. After this process, five micrometer thick sections
were prepared and stained by hematoxylin-eosin stain,
and the healing state of the tendon was assessed by light
microscopy. Histopathological state was evaluated by x100
magnification. Tenocytes, ground substance, amount of
collagen, vascularity (27) and presence of calcification were
the parameters assessed; scoring was performed using the
semiquantitative scoring system developed by Backman et
Findings obtained in the study were evaluated using the
SPSS Statistics 22 (IBM SPSS, USA) program for statistical
analysis. The normal distribution of the parameters was
assessed by the Shapiro-Wilk test when the study data were
evaluated. The Kruskal-Wallis test was used for comparison
of the groups with no normal distribution and the Mann-
Whitney U test was used for the determination of the group
causing the difference in the comparison of the quantitative
data. The Chi-square test was used for comparison of
qualitative data. Significance was assessed at **p<0.05.
There was a statistically significant difference between the
groups in terms of maximum load averages (p = 0.002). As
a result of the binary comparisons for differentiation, the maximum load averages in the Intact Saline group were
statistically significantly lower than the mean values of
Intact Corticosteroid (p = 0.016), Injured Saline (p = 0.001)
and Injured Corticosteroid (p = 0.012) groups. There was no
statistically significant difference between the other groups
in terms of maximum load averages. Statistical evaluation
results of biomechanical tests among the groups are shown
in Table I
. There was no statistically significant difference
between the groups in terms of maximum extension
averages. There was no statistically significant difference
between groups in terms of stiffness averages.
Click Here to Zoom
|Table I: Statistical evaluation of maximum load, maximum point elongation and rigidity parameters between groups.
All rat right legs underwent corticosteroid injection and
their controlled left legs were evaluated histopathologically
(Table II). (Figure 3A-D, Figure 4A-D).
Click Here to Zoom
|Table II: Statistical evaluation of histological parameters between groups.
Click Here to Zoom
|Figure 3: A) Normal appearance of the tendon in the intact saline group and B) cortisone group (H&E; x40). C) Chondroid differentiation
in the damaged cortisone group (H&E; x40). D) Vascularity in the injured saline group (H&E; x40).
Click Here to Zoom
|Figure 4: A) Chondroid differentiation (H&E; x40). B) Mucinous matrix (Alcian blue; x40). C) Enlargement and rounding of cell nuclei
in the damaged saline group (H&E; x100). D) Close to normal appearance in the damaged cortisone group (H&E; x40).
There was a statistically significant difference between
groups in terms of tenocyte mean values (p = 0.001). As
a result of the binary comparisons for discrimination,
tenocyte averages in the Intact Saline group were statistically
significantly lower than the Injured Saline and Injured
Corticosteroid groups (p = 0.001, *p<0.05, respectively).
Tenocyte averages in the Intact Corticosteroid group were
statistically significantly lower than those in the Injured
Saline and Injured Corticosteroid groups (p = 0.001;
There was no statistically significant difference in tenocyte
averages between the other groups. There was a statistically
significant difference between the groups in terms of the
average of the ground substance (p = 0.001). As a result of
the binary comparisons made to determine the difference;
The mean values of the ground substance in the Intact Saline
group were statistically significantly lower than the mean
values of the Injured Saline and Injured Corticosteroid
groups (p = 0.001, *p<0.05, respectively). The mean values
of the ground substance in the Intact Corticosteroid group
were statistically significantly lower than those of the Injured
Saline and Injured Corticosteroid groups (p = 0.001, *p<0.05,
respectively). There was no statistically significant difference
in the mean of the ground substance among the other groups.
There was a statistically significant difference in collagen
averages between the groups (p = 0.001). As a result of the
binary comparisons made to determine the difference; the collagen averages in the Intact Saline group were statistically
significantly lower than the Injured Saline and Injured
Corticosteroid groups (p = 0.001, *p<0.05, respectively). The collagen averages in the Intact Corticosteroid group
were statistically significantly lower than those of the
Injured Saline and Injured Corticosteroid groups (p = 0.001,
*p<0.05, respectively). There was no statistically significant
difference in collagen averages between the other groups.
There was a statistically significant difference between the
groups in terms of vascularity averages (p = 0.001). As a
result of the binary comparisons made to determine the
The mean vascularity in Intact Saline group was found to
be statistically significantly lower than the mean values of
the Injured Saline (p = 0.004) and Injured Corticosteroid
(p = 0.010) groups (*p<0.05). The vascularity averages
in the Intact Corticosteroid group were statistically
significantly lower than the mean values of Injured Saline
(p = 0.004) and Injured Corticosteroid (p = 0.010) groups
(*p<0.05). There was no statistically significant difference in vascularity averages between the other groups. There
was no statistically significant difference in calcification
distribution ratios between the groups.
In our study, we aimed to observe the positive or negative
effects of corticosteroids on healing with the reducing effect
of inflammatory actions in the damaged tissue and to show
whether corticosteroids could be used in injured Achilles
tendon in humans. According to the biomechanical test,
the maximum load averages in the Intact saline group
were statistically significantly lower than the mean values
of the Intact Corticosteroid, Injured Saline and Injured
Corticosteroid groups. In histopathological examination,
tenocyte averages in the first group were statistically
significantly lower than the mean of the Injured Saline
and Injured Corticosteroid groups. The mean values of
the ground substance in the Intact saline group were statistically significantly lower than those of the Injured
Saline and Injured Corticosteroid groups.
In our study, according to the biomechanical test and
histopathological examination, corticosteroids had positive
effects on healing in the injured Achilles tendon.
Treatment of Achilles tendinosis is still a subject of debate
and research is underway. In animal studies, there are more
than one way to create tendon degeneration 1. We believe
that the most appropriate one among these methods is the
Achilles tendon damage model proposed by Akamatsu et
al. (26). We preferred mechanical tendon damage instead of
chemical damage as substances that chemically damage the
Achilles tendon would interact with our corticosteroids. The
partial/complete rupture and repair model has been used
in many studies. However, in this model, it was concluded
that the repair of the lesion could not mimic the incidence
of Achilles tendinosis and subsequent healing after rupture
due to degeneration. Another controversial issue is whether
corticosteroids will be administered intratendinously or
into the paratenon. In relation to this, there are many studies
with various applications. In many experimental studies, it
has been found that the intratendinous administration of
steroid leads to a reduction in tendon strength by producing
significant amounts of collagen necrosis 19. Experimental
studies have shown that corticosteroids cause rupture risk
20 and degeneration even weeks later, leading to hypoxic
degenerative changes, especially when administered
intratendinously. Applications into the paratenon are
controversial 20. It has been reported that corticosteroids
may cause spontaneous tendon rupture with destruction
of the wound while reducing the symptoms present in
the tendon with an anti-inflammatory effect 21. Several
animal studies on the delaying effects of local corticosteroid
injection on tendon healing have been conducted. 0.1 ml
(0.7 mg) of corticosteroid injection is equivalent to a
normal 70 kg human dose 27. Corticosteroid injection has
been proven to be applicable to healthy tendons to model
experimental tendon degeneration. 0.1 mg/kg normal
human dose was also used in animal studies 27.
In the light of this literature information, we found it
appropriate to use the same dose. In this part of the study,
the tendon was disrupted before the injection into the intact
Achilles tendon in order to make sure that the injection
was intratendinous and corticosteroid injected. In Achilles
tendinosis healing, it is important that the functional
performance of the individual and success/failure decision
in treatment as well as the biomechanical properties of the
Achilles tendinosis is based on this clinical measure. In
clinical work, Achilles tendon function can be measured with the aid of static weight and dynamometer. Additional
biomechanical studies have shown that the functional
recovery and mechanical recovery of the recovering tendon
are similar 22.
In the biomechanical evaluation of the tendons obtained
after sacrification of the rats, the maximum load averages in
the Intact Saline group were statistically significantly lower
than in the other groups 23.
The gross macroscopic appearance of the Intact Saline
was already thin and consistently soft compared to other
groups. This group concluded that it affected the strength
of damaged tendons and lack of fibrosis in the intact tendon
group treated with corticosteroids 24.
In order to prevent this, it is reported that shortening of
the 1-month waiting period after the experiment can lead
to more accurate results in the case of shorter recovery
time 25. Although the etiology of Achilles tendinosis is
still being discussed, many studies have been conducted
to elucidate the inflammatory and degenerative properties
of the pathology. Although the underlying pathology of
chronic tendon lesions is degenerative, inflammation may
also be present in acute pathologies 26.
When this study was planned, semiquantitative
histopathologic examination taking into account the
tendon degeneration after tendon injury application and
the inflammatory changes was planned. In this study,
a method including parameters of tenocyte, ground
substance, amount of collagen, vascularity and calcification
suggested by Aydın et al. 27, which shows intratendinous
degeneration in histopathologically evaluated tendon
sections, was used.
Findings in this study are consistent with the literature.
The mean of the ground substance (extracellular matrix
elements secreted by the fibroblasts in connective tissue)
in the groups of intact tendon injections was statistically
significantly lower than that of the damaged tendon
groups. This result is related to the increase in the amount
of protein in repair tissue 27. Similarly, the mean amount
of collagen in groups of intact tendon injections was found
to be statistically significantly lower than that of damaged
In one study, thrombocyte-rich fibrin was shown in
supraspinatus tendons in rats and helped heal tendonbone.
In this study, test groups with and without fibrin
were compared. It was shown that those using fibrin
are stronger. Histological studies have also shown that
healing response and fibrous tissue production are greater
in the fibrin group. It has been suggested that this is due to collagen production in repair tissue 28. Also, the
vascularity averages in groups of intact tendon injections
were found to be statistically significantly lower than those
of the damaged tendon groups. However, Gigliotti et al.
have shown the exact opposite in their work 29. They
took a biopsy from torn and firm rotator cuff tendons in the
shoulder during arthroscopy and histologically examined
them. Tendon injury model used in our study is more acute
period compared in this study. The chronic process may
be considered to reduce vascularity, but this is a different
research topic. Although OBrien et al. 30 showed that
heterotropic ossification and calcification were triggered
and increased by trauma in the tendon-bone attachment
regions, no statistically significant difference was found
between the groups in terms of calcification in our study.
On the other hand, there was a statistically significant
difference in terms of tenocyte, ground substance, amount
of collagen and vascularity in our study. This is because
OBrien and his colleagues carried out studies on the bonetendon
junction rather than the intratendon area.
The use of corticosteroids is still controversial although
it is one of the most preferred drugs in the treatment of
Achilles tendinopathy. There is still no consensus on the
form of application, dose and total treatment duration
for tendons. There are many studies on tendinopathy
treatment. In a literature review, we found that these studies
were performed on intact tendons. Therefore, we decided
to choose a damaged tendon. At the end of our study, we
obtained biomechanical and histopathologic data showing
that the maximum load averages of damaged tendon
groups were higher. We think that this tendency is directly
proportional to the fibrosis of the healing tendon.
We believe that we should wait for a shorter period as the
one-month waiting period prior to sacrificing the rats
is long and results in excessive fibrosis. We also grossly
observed this. The damaged tendons were macroscopically
thicker and harder and thus more difficult to break.
The fact that the changes were not shown at the molecular
level and the results of the studies in the literature differed
from ours are considered as limitations of the present study.
The strengths of the study were that biomechanical and
histopathological evaluations were performed together
and histopathological evaluation was performed by a
CONFLICT of INTEREST
The authors declare no conflict of interest.
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