921589

research-article2020
IJLXXX10.1177/1534734620921589The International Journal of Lower Extremity WoundsJavanmardi et al

Original Article
The International Journal of Lower

Wound Healing Activities of Gundelia

Extremity Wounds
1­–10
© The Author(s) 2020
tournefortii L Extract and Milk-Cream Article reuse guidelines:
sagepub.com/journals-permissions

Ointment on Second-Degree Burns of DOI: 10.1177/1534734620921589

https://doi.org/10.1177/1534734620921589
journals.sagepub.com/home/ijl

Rat Skin

Setareh Javanmardi, PhD1, Iman Safari, MD1, Faranak Aghaz, MSc1 ,

and Mozafar Khazaei, PhD1

Abstract
Skin burn is a major health problem in the community and seeking new and suitable treatment is suggested. In this regard,
traditional remedies were consider in many countries. Regarding clinical application of herbal medicine in the healing of
burn wounds, the present study was designed to evaluate the effect of Gundelia (Gundelia tournefortii L) extract with milk-
cream on the healing of second-degree burn in a rat model. Thirty-six male Wistar rats (220 ± 30 g) were divided into 3
groups (n = 12), after establishment of second-degree burn: group1, were left without any intervention; group 2, were
treated topically with silver sulfadiazine; and group 3, were treated with Gundelia tournefortii L extract composite with
milk-cream once a day for 21 days. Macroscopically and histological examinations were conducted on 7, 14, and 21 days of
therapy. Data analyses were done using 1-way analysis of variance and post hoc Tukey tests. Macroscopically, evaluation
of wounds’ sizes on the 14th and 21st days indicated that the wound surface was reduced significantly (P < .001) in group
3 compared with groups 1 and 2. Histological findings also showed that burn healing was significantly improved in group 3
compared with the other groups. Gundelia tournefortii L extract composite with milk-cream has an effective role on healing
of second-degree burn in rat skin and it could a complementary and/or alternative medicine in wound healing.

Keywords
Gundelia tournefortii L, milk-cream, second-degree burn, rat, traditional medicine

Introduction
Burn wounds are among the most distressing of all injuries,
with many physical, mental, and serious complications if
not treated at the right time. More than 90% of fatal fire-
related burns occur in developing or low- and middle-
income countries.1 The degree of burn depends on the heat
temperature, contact time, and anatomical region of the skin
and classified by level of severity as I, II, and III grades.
The most common burns are the first-degree or superficial
burn, which is the least serious and causes tenderness simi-
lar to sunburn. The second-degree burn, known as partial-
thickness burns, can be superficial or deep and take more
than 2 weeks to heal.2
The second-degree burn wound is increasingly suscepti-
ble to bacterial infections, free radical damage, and inflam-
matory infiltration. So far, many antibiotics and topical
antimicrobial, antioxidant, and anti-inflammatory drugs have
been used in the control and treatment of burns, including
chemical medications such as silver sulfadiazine (SSD), sil-
ver nitrate, mafenide acetate, and bacitracin and mupirocin-α
ointment. Although these chemical medications, particularly
SSD, are widely used topically, its use requires frequent
dressing changes and can cause unwanted side effects:
adverse reaction and drug resistance.3,4
Skin burn is a major health problem in the community
and seeking new and suitable treatment is suggested.
Traditional remedies were considered in many countries.
Regarding clinical application of herbal medicine in the
healing of burn wounds, researchers have attempted to find
alternative natural source drugs. Some herbal plants having
burn wound healing properties have been described in
Chinese, Indian, and Iranian traditional medicine and have
been scientifically evaluated.
Gundelia tournefortii L, from the Asteraceae family, has
been identified as one of the traditional medicine plants with
1
Kermanshah University of Medical Sciences, Kermanshah, Iran
Corresponding Author:
Mozafar Khazaei, Fertility and Infertility Research Center, Health
Technology Institute, Kermanshah University of Medical Sciences,
Kermanshah, Iran.
Email: mkhazaei1345@yahoo.com
2 The International Journal of Lower Extremity Wounds 00(0)
various applications in Asian-temperate zones especially
Cyprus, Egypt, Jordan, Turkey, Turkmenistan, some regions
of Azerbaijan, North African countries, and Iran. G tourne-
fortii, locally known as “kangar” in Iran, is found as a wild
herb growing during late winter and early spring on the hills
of western, northwestern, south, and southeastern parts of
Iran.5,6 Traditionally, G tournefortii is used for treatment of
liver diseases, diabetes, chest pain, heart stroke, gastric pain,
vitiligo, diarrhea, and bronchitis. It is also reported that com-
pounds found in G tournefortii provide several pharmaco-
logical effects, for example, antibacterial, antii-inflammatory,
hepatoprotective, and antioxidant activities.7
High antioxidant activities are attributed to flavonoid
compounds of G tournefortii by radical scavenging activity
toward either reactive species or lipid peroxidizing radi-
cals.8 Anti-inflammatory and antinociceptive effects of
aerial parts of G tournefortii on male mice indicated that the
total extract had significant antinociceptive and anti-inflam-
matory effects.9 Therefore, it seems that G tournefortii can
be effective for managing second- and third-degree burns.
There have also been some traditional scientific studies on
the wound healing effects of milk that is rich in bioorganics
and minerals.10,11 These findings suggest that milk may be
used as the wound healing equipotent of burn injuries.
Unfortunately, there are few or no literature publications on
the effects of G tournefortii or milk-cream, or their mixture,
on second-degree burn injuries. Therefore, the present study
aimed to assess wound healing effect of G tournefortii and
milk-cream, in the ointment form, on second-degree burn
injuries of skin of rat.
Material and Methods
Animals
Wistar rats (220 ± 30 g and 10 weeks age) were housed in
cages (20°C to 23°C, 30% to 80% humidity, 12-hour light/
dark cycle) and allowed free access to water and food ad
libitum. After 1 week acclimatization, they were randomly
divided into 3 groups (n = 12 per group) as follows: (1) the
control group (the burned area was left without any inter-
vention); group 2: was treated topically with silver sulfadia-
zine (SSD) 3%; and group 3: was treated with Gundelia
tournefortii L composite with milk-cream, as an ointment,
once a day. All experiments were performed according to
International Guidelines for Animal Ethics and Use and
approved by the Kermanshah University of Medical
Sciences Animal Ethics Committee (Approval No: KUMS.
REC.1395.645).
Second-Degree Burn Wounds
The animals were anesthetized using ketamine (100 mg/kg)
and xylazine (10 mg/kg). After removing the hair at the
back with an electric shaver, the skin was washed with 10%
iodine for disinfection. To create deep standard second-
degree burn wound on the back of the rats, a circular device
of 2.5-cm diameter (with the same size about 20% total
body surface area)12 was made by the researcher in the labo-
ratory. The metal stump or plate was heated to a flame for 5
minutes and placed on the back of the animal for 8 seconds.
In order to produce similar burns, the pressure on the skin
was the same in all rats. Medications or our ointment were
applied instantly and repeated once daily, and to determine
the wound healing, 2 methods of morphological and histo-
logical evaluation were used.
Ointment Preparation
Gundelia tournefortii L (Asteraceae) is a perennial spiny
native plant grown extensively in the west of Iran,
between the months of March and April. G tournefortii
aerial parts consisted of the leaves and stems collected (in
one of its natural habitat in Central Zagros, Iran), during
the flowering period and the vegetative phase. The air-
dried aerial parts of G tournefortii L were burned and
mixed with milk-cream (GT/MC) as ointment. Thus, G
tournefortii L extract and milk (4:1) are mixed to make
ointment.
Morphological Evaluations
The wounds were examined every 24 hours for any mor-
phological changes in appearance of wounds and any
necrotic tissue was removed. Pictures were taken using a
digital camera on days 7, 14, and 21 after the day of burn
induction (day 0) and were evaluated by Image device soft-
ware (motic 2000), which offered us an indirect tool to
measure the burn wound area of each rat. The morphomet-
ric analysis of pictures, including fibroblast and blood den-
sities (as a ratio of fibroblast or vessel counts per 1 mm2
area at 40× magnification), percentage wound area, tissue
necrosis, and epidermal thicknesses, and collagen fiber
arrangement in the dermis, were done.
The dimensions of wound from the day of burn (day 0)
to the 21st day for all groups was measured with a ruler
based on millimeters in the whole time intervals of the
wound (Figures 1-3). The data were entered in MS Excel
program and each wound dimension was determined using
the horizontal diameter × vertical diameter × π formula.
Using the following formula, the wound healing percentage
in each rat was determined:
Woundsurface on the
mentioned day
Wound percentage = 100 ×
Surface on thefirst day
Wound healing percentage = 100−wound percentage
Javanmardi et al 3
Figure 1.  Comparison of the dimensions of the wound
in different time intervals of 7, 14, and 21 days and various
treatment groups of Gundelia tournefortii L and Milk-Cream
Ointment group, silver sulfadiazine, and the control. *P < .05.
***P < .0001, 1-way analysis of variance.
Figure 2.  Comparison of the percentage of burn wound
healing in different time intervals of 7, 14, and 21 days and
various treatment groups of Gundelia tournefortii L and Milk-
Cream Ointment group, silver sulfadiazine, and the control.
Histological Evaluations
The animals were euthanized in time intervals of 7, 14, and
21 days after therapy and tissue samples (2-3 mm) were
taken from the edges of burn wounds using a biopsy puncher.
The samples then were fixed in 10% formalin, dehydrated in
alcohol, molded in paraffin, and 5-µm sections were pre-
pared for histological evaluation. Then hematoxylin and
eosin and Masson trichrome staining of tissue sections was
performed for investigation of scoring criteria such as reepi-
thelialization, formation of collagen fibers and granulation
tissue, inflammation, and edema (Figures 4-8). Microscopic
images of sections were taken using a light microscope
equipped with a digital camera (Moticam, model A-352,
Spain). Histopathological evaluation and scoring was done
as per the method described by Tkalčević et al12 (Table 1).
Granulation tissue was described as follows:
A (no/less inflammation): Epithelial tissue formation,
less inflammation, no leukocyte infiltration, high density
of collagen bundles, and normal capillary bed
B (moderate acute inflammation): Epithelial and granu-
lation tissue formation, leukocyte infiltration, formation
of collagen bundles, formation of capillary networks
C (sever acute and chronic inflammation): Granulation
tissue with epithelial formation, sever leukocyte infiltra-
tion, capillary networks destruction, and edema
Also comparison of grading score for various histomor-
phological changes in various treatment in and different
time intervals of 7, 14, and 21 days groups of Gundelia
tournefortii L and Milk-Cream Ointment group, SSD, and
the control are shown in Table 2. The score for each histo-
pathological parameter was given in a semiquantitative
manner with grades of 0 to 5, where 0 is lowest and 5 is
highest scale for each histopathological parameter (*P <
.05. ***P < .0001, 1-way analysis of variance).
Statistical Analysis
Data were expressed as the mean ± standard deviation and
were analyzed using SPSS software (version 16, Chicago,
IL). Data were tested for normality analysis of the parame-
ters with the Kolmogorov-Smirnov test. One-way analysis
of variance followed by Tukey’s test for multiple compari-
sons was used to determine statistically significant differ-
ences between groups. Also, qualitative data were analyzed
by the nonparametric Kruskal-Wallis method followed by
the Mann-Whitney U test. P ≤ .05 was considered to be
statistically significant.
Results
Morphological Evaluations
Morphological evaluations on days 7, 14, and 21 showed that
the healing process and wound size reduction rates were bet-
ter in the GT/MC (Gundelia tournefortii L and Milk-Cream
Ointment group) ointment and SSD groups in comparison
with the control group (Figures 1 and 2). A decrease in wound
size at 7 days was seen in GT/MC ointment and SSD groups,
but there was no significant difference among groups regard-
ing the wound areas. On day 14, the difference was statisti-
cally significant between GT/MC ointment group when
compared with SSD (P < .001) and control groups (P =
.001), respectively. At the end of week 3 (day 21), significant
differences were observed between 3 groups (Figure 3). On
the other hand, the result indicated that GT/MC ointment-
treated group had slight healing effects and could shorten the
recovery time of burns’ wounds comparing to the control
group and SSD group (P < .001).
Histological Evaluations
In histopathological analyses of specimens indicating a reduc-
tion in necrosis and inflammation, there was a decreasing
4 The International Journal of Lower Extremity Wounds 00(0)

Figure 3.  Comparison of the percentage of burn wound healing and the macroscopic wound healing process in various treatment
groups of Gundelia tournefortii L and Milk-Cream Ointment group, silver sulfadiazine, and the control with regard to the time in
different time intervals of 7, 14, and 21 days. (A) Burn on the first day, (B) burn on the 7th day, (C) burn on 14th day, and (D) burn on
the 21st day.

process after day 7 without any significant difference between
groups on days 7 and 14, but on day 21, the difference was
statistically significant between GT/MC ointment and SSD-
treated groups when compared with the control group. There
was slight acute inflammation in GT/MC ointment group,
moderate acute inflammation in SSD, and a mixture of intense
acute and chronic inflammation in the control group (Figures
4 and 5).
Also the best result for reepithelization, scrab scab, gran-
ulation tissue formation, total volume of collagen fibers for-
mation rates, and adipose tissue were observed on day 21
for the G tournefortii and milk-cream ointment and SSD
groups. Reepithelization rate by the G tournefortii and
milk-cream ointment was insignificantly higher than SSD
and control groups (Figure 6). Total volume of collagen
fibers in the GT/MC ointment group were significantly
higher than control group at day 21. Lengths density of
blood vessels (BC) in comparison were ~40% at SSD group,
80% at GT/MC, and 60% at control group. Scar Scab for-
mation had covered more than 50% of the wounds in the
GT/MC ointment and SSD groups; but in control group, the
ratio was <50%. In fact, wound healing effects of the GT/
MC ointment group was much better in comparison with
SSD group (Figure 6).
Discussion
In summary, for the first time, the present study showed that
the G tournefortii L and milk-cream has proven as an effec-
tive wound dressing ointment for second-degree burn
wound and could shorten the recovery time of burn wounds
comparing to the control and SSD groups, in Wistar rats.
Improving the wound healing progresses is of great impor-
tance for burn injuries.
Free radical damage and inflammatory infiltration are 2
major contributing factors to burn wound progression.13 To
alleviate this factor, special attention has been provided to
the addition of chemical medications to improve the inhibi-
tion of excessive inflammation and reduce free radical gen-
eration. The anti-inflammation activity of SSD is likely to
Javanmardi et al 5

Figure 4.  Treatment of the of Gundelia tournefortii L and Milk-Cream Ointment group on burn rats using morphology evaluation and
histological evaluation (day 7). (A) Control group; (B) silver sulfadiazine group; (C) Gundelia tournefortii L and Milk-Cream Ointment
group. AT, adipose tissue; IF, inflammatory cells; CR, scar scab; B, bleeding.

be the main reason of its common administration.14 Previous
reports suggest that silver-based products are better to be
avoided due to their side effects. The investigators are mak-
ing efforts to detect natural source drugs, topical anti-
inflammation products. G tournefortii L is one of the herbal
plants whose anti-inflammatory and antioxidant activities
are being tested.7
Reactive oxygen species generation or oxidative stress
plays an important role in delay of wound healing and con-
tributes into poor outcomes.2 Treatment with antioxidants
reinforces cellular antioxidant defense mechanisms, might
decrease free radical–mediated damage, and minimize
tissue destruction during burn injury and can also accelerate
the process of wound healing. Unfortunately, antioxidant
therapy does not have any clinical implication till now.15
The anti-inflammatory and antioxidant activities of the G
tournefortii L have been previously reported.16
High antioxidant activities are attributed to gallic acid
and quercetin, typical flavonoids of G tournefortii L, which
are expected to take part in inhibition of cytochrome P450,
leading to CCl4 metabolism to reactive free radicals.
Flavonoids’ antioxidant activities are exerted in different
ways, including radical scavenging activity toward either
reactive species or lipid peroxidizing radicals; inhibition of
6 The International Journal of Lower Extremity Wounds 00(0)

Figure 5.  Treatment of the of Gundelia tournefortii L and Milk-Cream Ointment group on burn rats using morphology evaluation and
histological evaluation (day 14). (A), Control group; (B) silver sulfadiazine group; (C) Gundelia tournefortii L and Milk-Cream Ointment
group. EP, epithelialization; IF, inflammatory cells; CR, scar scab.

production of reactive species through metal chelation; and
interaction with other antioxidants, localization, and mobil-
ity of the antioxidant at the microenvironment.7 It has also
been reported that chromogenic acid is an important con-
stituent of G tournefortii L, identified to be a scavenger for
reactive species of nitrogen and oxygen and an inhibitor
against the formation of conjugated diene from the linoleic
acid oxidation.5 G tournefortii, due to chromogenic acid,
decreases atherosclerosis, reducing lipid, lipoproteins, and
lipid peroxidation.17
Recently, it has been suggested that G tournefortii has
tocopherols (are natural antioxidants), fatty acids, and
sterols. These findings present G tournefortii as antioxidant
compounds. The present results indicated, for the first time,
that G tournefortii L and milk-cream ointment had optimal
healing effects and could shorten the recovery time of burn
wounds compared with the control group and SSD group in
Wistar rats. However, the antioxidant effects of G tourne-
fortii L could be one of the reasons responsible for the
improvement of the healing effects and could shorten the
recovery time of burn wounds compared with the control
group in the present study.
On the other hand, G tournefortii improved the healing
of wounds in second burn, thereby preventing oxidative
Javanmardi et al 7

Figure 6.  Treatment of the of Gundelia tournefortii L and Milk-Cream Ointment group on burn rats using morphology evaluation and
histological evaluation (day 21). (A) Control group; (B) silver sulfadiazine group; (C) Gundelia tournefortii L and Milk-Cream Ointment
group. EP, epithelialization, IF, inflammatory cells, CR, scar scab; B, bleeding; AT, adipose tissue; GT, granular tissue; CF, collagen fiber;
BC, blood cell.

stress, and that the mechanism of this antioxidant action is
the radical scavenging activity toward either reactive spe-
cies or lipid peroxidizing radicals; inhibition of production
of reactive species through metal chelation; and interaction
with other antioxidants, localization, mobility of the anti-
oxidant at the microenvironment, due to the remarkably
high content of flavonoids and the presence of other com-
pound such as chlorogenic acid and tocopherols in G
tournefortii L.7,18
Inflammatory is known to be a contributing factor to
burn wound progression.13 Recently, it has been suggested
that anti-inflammatory production may play an important
role to help reduce burn injury progression.13 Oryan et al
showed the anti-inflammatory and antinociceptive effects
of aerial parts of G tournefortii on male mice, which might
imply a beneficial effect of this traditional medicine plant
on wound healing progresses.9
In the present study, treatment of rats with GT/MC
improved the wound healing progresses compared with that
of the SSD group. It can be speculated that the beneficial
effects of G tournefortii L in the wound healing progresses
are through anti-inflammatory activity. These findings pres-
ent new aspects of the role of GT/MC during wound healing
progresses and give a scientific basis for new treatment
ointment formulation.
This study was an experimental research, and there
were a few limitations. First, limitations of this study
include its small size and that the assessors were not
8 The International Journal of Lower Extremity Wounds 00(0)

Figure 7.  Hematoxylin and eosin staining of normal skin tissue and burn wounds. EP, epiderm; D, derm; HF, hair follicle; H, hair; SG,
sebaceous gland; SC, stratum corneum.

Figure 8.  Hematoxylin and eosin staining of second-degree burn wounds. The accumulation of dead and damaged cells on the
surface of the wound. (A) Blood clots due to blepharoplasty of the dermis with low infiltration of inflammatory cells. (B) The presence
of inflammatory cells in the healthy part of the skin dermal region of the burn wound (C) on the first day after burn and before the
intervention.
Javanmardi et al 9

Table 1.  Defined Scoring Parameters Assessed for the Histological Evaluations.

Score Score Defined

No/less inflammation
Moderate acute inflammation
Sever acute and chronic inflammation
Epithelial tissue formation, less inflammation, no leukocyte infiltration, high density of
collagen bundles, normal capillary bed
Epithelial and granulation tissue formation, leukocyte infiltration, formation of collagen
bundles, formation of capillary networks
Granulation tissue with epithelial formation, severe leukocyte infiltration, capillary
networks destruction, edema

Table 2. Histopathologicala Grading Score for Various Histomorphologicalb Changes in Difference Group.

Epithelial Granulation Formation Formation

Tissue Tissue Leukocyte of Collagen of Capillary
Group Formation Formation Infiltration Bundles Networks Inflammation P
Day 1
  Control group 5 5 5 0 0 5 —
  Silver sulfadiazine group 5 5 5 0 0 5 —
  Gundelia tournefortii L and 5 5 5 0 0 5 —
Milk-Cream Ointment group
Day 7
  Control group 4 4 5 1 1 4  
  Silver sulfadiazine group 4 4 3 2 2 3  
  Gundelia tournefortii L and 3 3 3 4 3 3 *
Milk-Cream Ointment group
Day 14
  Control group 3 3 4 2 3 3  
  Silver sulfadiazine group 3 3 2 3 4 3 *
  Gundelia tournefortii L and 2 2 1 5 4 2 ***
Milk-Cream Ointment group
Day 21
  Control group 1 2 2 3 4 2  
  Silver sulfadiazine group 1 1 1 4 5 2 *
  Gundelia tournefortii L and 0 0 0 5 5 0 ***
Milk-Cream Ointment group
a
The score for each histopathological parameter was given in a semiquantitative manner with grades of 0 to 5, where 0 is lowest and 5 is highest scale
for each histopathological parameter.
b
Comparison of grading score for various histomorphological changes in various treatment in and different time intervals of days 7, 14, and 21 groups
of Gundelia tournefortii L and Milk-Cream Ointment group, silver sulfadiazine, and the control.
*P < .05. ***P < .0001, 1-way analysis of variance.

blinded to the treatment. Second, it remains to be tested Declaration of Conflicting Interests

whether the GT/MC has proven as wound healing pro-
gresses for third-degree burn wound in rats and clarify
pathways influenced by GT/MC ointment for second- and
third-degree burn wound. Also, we should have tested
whether the GT/MC can be an effective wound dressing
ointment during third-degree burn. So, future larger stud-
ies will be necessary to confirm our findings for both
degrees of burn.
Conclusion
It was concluded that GT/MC ointment significantly accel-
erated the wound healing process in the second-degree burn
wound in an experimental rat model.
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Faranak Aghaz https://orcid.org/0000-0002-7311-4071
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