OPEN ACCESS International Journal of Pharmacology

ISSN 1811-7775
DOI: 10.3923/ijp.2020.18.26

Research Article
Role of Bovine Fetal Platelet-rich Plasma (PRP) on Skin Wound
Healing in Mice
1
Mardin O. Mohammed, 1Osman J. Ali, 1Sozan A. Muhamad, 2Salam H. Ibrahim, 3Goran M. Raouf and
2
Nadia A. Salih

1
Department of Surgery and Theriogenology, College of Veterinary Medicine, University of Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq
2
Department of Basic Sciences, College of Veterinary Medicine, University of Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq
3
Department of Pathology and Forensic medicine, College of Medicine, University of Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq

Abstract
Background and Objective: Platelet-rich plasma is the portion of the blood plasma which contains platelet concentration beyond usual
levels. It is a new method to stimulate tissue regeneration response as it contains a wide range of growth factors that enhance wound
healing and tissue repairing mechanism. This study was aimed to investigate the impact of concurrent application of topical and
subcutaneous (S/C) infiltration of PRP at the excised wound boundaries upon epidermal surgical lesions. Materials and Methods: A clean
epidermal incision of 5 mm in diameter was made in the back region of each mouse (n = 20). Animals were divided in 2 groups,
group 1 (n = 10) were left untreated (control group), while group 2 received bovine fetal. Wounds were topically and subcutaneously
infiltrated with PRP for 21 days. Wound healing measurement, percentage of wound contraction and histopathological investigation of
the wounds from skin biopsy were evaluated, both in treated and un-treated mice at 3rd day, 7th day, 14th day and 21st day post
wounding. Results: There was an obvious progress in wound healing response at 14th day of PRP treatment and complete healing after
21 days of PRP treatment, comparing to the control group. Also, the percentage of epithelization and wound contraction were significantly
increased in PRP-treated mice at any period of time, comparing to control group. Histopathological results showed higher granulation
tissue formation, new blood vessel formation and collagen synthesis. Conclusion: The PRP could be useful to enhance wound repair and
reduces scar tissue formation in surgically-induced excised skin wounds.

Key words: Platelet-rich plasma, wound healing, skin wound, tissue injury, tissue epithelization, angiogenesis, skin erosions

Citation: Mardin O. Mohammed, Osman. J. Ali, Sozan A. Muhamad, Salam H. Ibrahim, Goran M. Raouf and Nadia A. Salih, 2020. Role of bovine fetal
platelet-rich plasma (PRP) on skin wound healing in mice. Int. J. Pharmacol., 16: 18-26.

Corresponding Author: Nadia A. Salih, Department of Basic Sciences, College of Veterinary Medicine, University of Sulaimani, Sulaymaniyah,
Kurdistan Region, Iraq

Copyright: © 2020 Mardin O. Mohammed et al. This is an open access article distributed under the terms of the creative commons attribution License,
which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Competing Interest: The authors have declared that no competing interest exists.

Data Availability: All relevant data are within the paper and its supporting information files.
 Int. J. Pharmacol., 16 (1): 18-26, 2020
INTRODUCTION
Wound healing is a physiological process that empowers
the injured tissue to renovate its integrity and replace the lost
tissues1. Wound is caused by a disruption in the cellular
continuity of dermal tissue by chemical, physical, thermal,
microbial, or immunological injury to the tissue, which leads
to distraction of the structure and function of underlying
normal tissue2. There are a wide range of blood cells that play
an essential role in the process of wound healing including
cytokines and growth factors that play vital role in the renewal
of normal structure and function of the injured tissue3.
There are 3 major stages that involve in the process of wound
healing which include inflammation, new tissue formation
(granulation and angiogenesis) and tissue restoration4. In
addition, these 3 stages comprise of disciplined collaborations
between numerous cell types such as leukocytes, fibroblasts
and keratinocytes and are controlled by several factors,
including cytokines, chemokines, growth factors and enzymes.
After the early hemostasis, inflammation plays a vital role in
the normal process of wound healing. However, it has been
shown that sustained inflammation prevents entering into the
proliferative phase and delays wound healing process 4,5.
Furthermore, it has been shown that various factors play
an essential role in delaying the process of wound healing
through influencing of broken tissue, such as repeated injury,
infection, oxygenation and free radical creation. The process
of wound healing could be delayed and negatively affected by
the presence of free radicals, which can destroy wound
neighboring cells, or by infectious microorganisms6. Recently,
in vivo studies have shown that Platelet-rich plasma (PRP) can
significantly suppress the expression of pro-inflammatory
genes, suggesting that PRP would potentially impede the
inflammation7. It has also been shown that PRP plays a key
role in therapeutic application in tissue regeneration and
engineering as it contains high amount of growth factors with
potential mitogenic and anti-inflammatory activity8,9. In
addition, PRP is a congregation of platelets (3-5 fold the
plasma baseline level), which contains many growth factors
including transforming growth factor $1 (TGF-$1) and TGF-$2,
platelet derived growth factors (PDGFAA, PDGF-BB, PDGF-AB),
insulin-like growth factor 1 (IGF-I), epidermal growth factor
(EGF), vascular endothelial growth factor (VEGF), fibroblast
growth factor (FGF) and hepatocyte growth factor (HGF) that
are very important for regeneration processes. Moreover,
these growth factors synergistically increase the
infiltration of neutrophils and macrophages to enhance
angiogenesis, fibroplasia, matrix deposition and eventually
re-epithelialization, enhancing the subsequent tissue
19
regeneration8,9. Likewise, the presence of anti-inflammatory
substances, including HGF, reinforces the capability of PRP to
prevent inflammatory process10.
Furthermore, platelets are non-nucleated cell elements in
the blood that results from megakaryocytes fractionation in
the bone marrow11. Intracellularly, there are a wide range of
reservoir organelles in platelets, including lysosomes, alpha
granules and dense granule. The alpha granules, which are
found in copious supply, contain various proteins that play a
vital role in stimulating platelet adhesion and aggregation,
antimicrobial activity and tissue healing12 whilst the dense
granules are considered to play a crucial role in platelet
function. In addition, the alpha granules of platelets play a
vital role in the activation and secretion of important
biomolecules in the clot, including growth factors,
coagulation factors, platelet-specific proteins, adhesion
particles, cytokines, angiogenic factors, proteoglycans and
cytokines/chemokines13. Recent study has shown that
secretion of cytokines, chemokines and growth factors from
platelets persuade proliferation and activation of cells that are
essential for wound healing, such as fibroblasts, neutrophils,
monocytes, smooth muscle cells and mesenchymal stem
cells (MSC)14. Approximately 14 million surgical operations are
performed in the field of obstetric, musculoskeletal, urological
and gastrointestinal tract each year; thus wound healing will
remains to be most crucial both for the surgeon and
patient12,14. Most recent study has shown that platelet-rich
plasma, or platelet concentrate, is a potential adjuvant therapy
to enhance the process of wound healing15. Research on
wound healing mediators is one of the developing areas in
modern biomedical sciences and many studies have been
conducted using different wound healing models7. Thus,
the specific aim of this study was to investigate the healing
activity of PRP on the induced excised wound in animal model.
MATERIALS AND METHODS
This study was conducted from January to July, 2019 in
College of Veterinary Medicine, University of Sulaimani,
Kurdistan region, Iraq.
Animals: Twenty adult healthy mice (about 3 months old,
male, body weight approximately 30 g) were used in this study
for wound healing model experiments16. The animals were
obtained from animal house laboratory, College of Veterinary
Medicine, University of Sulaimani, Kurdistan region, Iraq and
housed, in standard cages and hygienically maintained in
veterinary teaching hospital. All animals had free access to
standard chow and drinking water and were maintained on a
 Int. J. Pharmacol., 16 (1): 18-26, 2020

12 h light/dark cycle with adequate ventilation. This study was the plasma-enriched platelets were pelleted by a hard
carried out in strict accordance with the recommendations centrifugation of buffy coat plasma at 3875 RPM for 5 min. The
approved by the committee on the ethics of animal, prepared PRP was carefully collected and aliquoted, then
University of Sulaimani, College of Veterinary Medicine. stored at -80EC for future use15-17.
All surgeries were performed under ketamine Administration of PRP, in treated animals with excised
(30 mg kgG1)/xylazine (20 mg kgG1) anesthesia, which was wound, was performed by application of 0.25 mL of PRP from
administered as a mixture at a dose of 0.01 mL gG1 body the aliquot onto the wounds, both by directly applying
weight via intraperitoneal injection and all efforts were made topically onto the wounds (first half of 0.25 mL) and via
to minimize pain. An excision wound, scarred areas 5 mm in subcutaneous injection (second half of 0.25 mL) in to the
diameter, by a longitudinal incision of the skin on back of each margin of the wounds (Fig. 1).
mouse was created. The animals will randomly allocate into
Measuring the percentage of wound contraction: The
four groups of 5 animals/each group.
measurement of wound contraction was performed, using
imageJ software, on the ruler-calibrated images16,17 (Fig. 2).
Preparation of platelets rich plasma (PRP): In this study,
cow s fetal umbilical cords (CUC) were collected from
slaughtered cows in Sulaimani slaughterhouse on
March-Jun, 2019 in Sulaimani city-Kurdistan region, Iraq.
Then the umbilical cord blood was taken directly from cow
umbilical cord artery, using sterile syringes and needle and
collected into a sterile bag containing an anticoagulant to
prevent clotting.
The platelet-rich plasma (PRP) was synthesized from the
collected umbilical cord blood and concentrated using a
series of centrifugations in the research center of college of
Veterinary Medicine-University of Sulaimani. The cord blood
was collected in acid-citrate dextrose+adenine (AcD-A) coated
collection tubes and initially centrifuged at 2000 RPM for 5 min
to separate the red blood cell (RBC) portion from the
platelet-rich plasma. The upper layer of the RBC portion,
a PRP layer (buffy coat), was comprised as the platelets
containing the largest amount of growth factors. Then, Fig. 1: Application of PRP

Fig. 2: Steps required for measurement the size or area of the wound in imageJ. After setting the scale, the freehand selection
tool was selected to outline the wound area (circle). By selecting the measure tool from the analyze tool bar the outlined
area of each wound was determined

20
 Int. J. Pharmacol., 16 (1): 18-26, 2020
Table 1: Histological grading criteria for wound healing according to Shafer criteria17
Grade 1 (very light healing) Grade 2 (moderate healing)
Low collagen content, scarce vascularity Moderate collagen content,
or low number of capillaries, absence number of capillaries, onset of
of granulation tissue abscess granulation tissue formation,
formation, necrotic epithelium epithelial proliferation
The image was opened or dragged into the ImageJ software
and then the straight-line selection tool was used to drag a
line across the calibrated ruler on the image in order to specify
a distance (e.g., 1000 µm). Then, setting the scale by clicking
the Analyze tool, the set scale window was opened that show
the length of the dragged line (e.g., 1000 µm) in pixels, which
could then be converted to a specified micrometers (µm),
The size of the wounds (areas) was measured using the
freehand selection tool and outlining the wounds (Fig. 2). By
selecting the measuring tool the outlined area of each wound
was determined. The wounds were measured from the
1st-21st day in both control and treated groups. Then the
percentage of wound contraction were taken from the 3rd day
by subtracting the measured size of the wounds from the
3rd, 7th, 14th and 21st from the size of the wounds from the
1st day of the operation and the area of each lesion was
calculated. Percent contraction of area was calculated, using
the following equation18,19:
Area in day 0-Area in analyzed day
Contraction (%) =  100
Area of day 0
Histopathological examination: Histopathological analysis
are performed within tissue specimens and skin samples were
collected from treated and control groups on day 3, 7, 14 and
21. The samples were fixed in 10% PBS buffered formalin
solution more than 7 days for histopathology study.
Six-micron-thick sections of the surrounding skin were stained
with H and E for light microscope. Histological state of the
healing wound was analyzed by assessing a wide range of
wound healing parameters of skin cells, including collagen
content, vascularity or number of capillaries, granulation
tissue, abscess formation, necrotic epithelium. The total
healing score for wound healing in each case was calculated
by adding the scores of individual criteria according to
Shafer et al.18 and Aragon-Sanchez et al.19. Accordingly, the
grading system was ranged from grade 1 (very light healing),
grade 2 (moderate healing), grade 3 (advanced healing) and
4 grade (well-organized) (Table 1).
Statistical analysis: All results are presented as Mean±SD
where n is the number of experiments. For data presentation
and statistical analysis, ImajeJ and GraphPad Prism 4 software
(GraphPad Software, USA) were used for statistical analysis
and either a Student s t-test (unpaired), one-way ANOVA
21
Grade 3 (advance healing) Grade 4 (well-organized)
Abundant collagen content, Fibrous connective tissue,
abundance of capillaries, presence of normal amount of capillaries,
a well-organized granulation tissue, absence of granulation tissue,
continuation of epithelialization complete epithelialization
(with Tukey s multiple comparison post-test) used where
applicable. The p<0.05 were considered statistically
significant.
RESULTS
PRP enhances the skin wound closure: The physical
condition of the animals were good in both control and
treatment groups. The physical activities of the animals,
including feeding, drinking, defecation, urination, alert and
brightness after creation of the wounds were approximately
normal and similar both in control and treated groups.
Digital photographs of wounds were taken at
days 0, 3, 7, 10, 14, 21 and 28. Time to wound closure was
defined as the time at which the wound bed was
completely re-epithelialized and filled with new tissue.
Moreover, postoperative complications such as inflammation
and abscess formation were not observed in all control and
treated mice. The induced skin wounds appeared dry,
crusted, erythematous without exudate and regressed slowly
until loss of surface layer and epithelialization. Healing of the
wounds was passed through the principles steps of wound
healing, where, the size of the wound started to decrease
from the 3rd day after the operation in PRP treated mice
comparing to control group. However, from the
3rd-7th day post treatment with PRP, there was no obvious
difference in wound healing size between the treated and
control groups.
However, there was remarkable improvement in skin
wound healing after 14th days of treatment in PRP treated
mice the comparing to the control group. Interestingly, at the
end of experiments on the 21st day of treatment, there was
complete closure of the skin wound in PRP treated mice
comparing to control mice, where a small amount of scar
tissue was left at the site of the wound (Fig. 3), the visual scar
area was carefully circled on the images of wound. This implies
that PRP play an important role in the healing process of
induced excised wound in mice after 21st days of treatment
with PRP.
PRP augmented the percentage of skin wound healing:
In this study, the percentage of wound contraction was
assessed during the different periods of wound treatment
with PRP. According to ImageJ criteria on the basis of
measuring the size of the wounds from 1st-21st day of study,
 Int. J. Pharmacol., 16 (1): 18-26, 2020

(a) (b)

1st day

3rd day

7th day

14th day

21st day

Fig. 3(a-b): Experimental wound on the back of the mouse in (a) Control and (b) Treatment groups at different stages of healing
from the 1st-21st day
There is a noticeable progress in wound healing from the 14th day and complete healing on 21st day in the treatment group when compared to the
control group, n = 10 for each group

22
 Int. J. Pharmacol., 16 (1): 18-26, 2020

it was found that the size of the wound were decreased
progressively in each group from the 3rd-21st day. When
these measurements in both groups compared, there was a
significant difference in the percentage of wound contraction
in the treated group (n = 3, p<0.05) comparing to the control
group (n = 3). As shown in Fig. 4, results showed that the
average percentage of wound contraction with their standard
deviation was significantly increased in the treated group on
the 3rd day (23±2.10%), 7th day (54.13±11.23%), 14th day
(80.72± 5.60) and 21st day (100%), respectively, using
Mann Whitney unpaired T-test (p<0.05), comparing to the
percentage of wound contraction in control group on the
absence of granulation tissue, severe abscess formation,
severe necrotic epithelium, both in the PRP treated and
untreated mice. In addition, histological observation,
both in the PRP treated and un treated mice, at 7th days
post wounding showed grade one of wound healing
(very light healing) with low collagen content, scarce
vascularity or low number of capillaries, absence of
granulation tissue, abscess formation and necrotic
epithelium (Fig. 5).
100 Control
Treatment

Wound contraction (%)

90
3rd day (11.86±0.86%), 7th day (22.83±4.14%), 14th day
80
(45.77±7.44%) and the 21st day(87.02±6.08%), respectively.
In order to further emphasize the statistically significant 70
differences (p<0.05) in the percentage of wound contraction,
60
in different days, between PRP treated and untreated mice,
histological examination and scoring of the wound were 50
3rd 7th 14th 21st
under taken.
Days

Microscopic observation of wound healing from histological
sections: The histological analysis for wound healing after
3rd day of PRP treatment in mice with excised skin wound
showed almost no healing with the same histological grade
comparing to positive control group. Histological results
showed that there is no collagen content, no capillaries,
Fig. 4: Percentage of wound contraction between the control
(n = 3) and the treatment group (n = 3) at 3rd, 7th, 14th
and the 21st days
There were a significant difference in the percentage of wound
contraction in treatment group when compared to the control group
using Mann-Whitney unpaired t-test (p<0.05) (Error bars = Standard
deviation), n = 10 for each group

(a) (b)

(c) (d)

Fig. 5(a-d): Histopathological changes of healed skin wounds at various period of post wounding in PRP treated and un-treated
mice. (a) Control group (3rd day post wounding), (b) Treated group (3rd day post wounding) (c) Control group
(7th day post wounding) and (d) Treated group (7th day post wounding)
White arrow (a-b): Ulcer site with necrotic epithelium covered by fibrinopurulent material, no collagen content, no capillaries, absence of granulation
tissue, White arrow (c-d): New capillary formation, low collagen content, low number of capillaries, abscess formation

23
 Int. J. Pharmacol., 16 (1): 18-26, 2020

(a) (b)

(c) (d)

Fig. 6(a-d): Histopathological changes of healed skin wounds in PRP treated and un-treated mice. (a) Control
group (after 14th day) shows low collagen content, low number of capillary, (b) Treated group (after 14th day) shows
moderate collagen content moderate collagen content, moderate number of capillaries, onset of granulation tissue
(white arrow), (c) Control group (after 21st day) shows moderate collagen content, moderate number of capillaries
and onset of granulation tissue formation (white arrow) and (d) Treated group (after 21st day) show abundant
collagen fibers, abundance of capillaries, well organized granulation tissue (white arrow)

However, histological sections from the 14th days of
wounds healing in PRP treated group showed grade 2 of
wound healing (moderate healing) with moderate collagen
content, moderate number of capillaries, onset of granulation
tissue formation, no abscess formation and no necrotic
epithelium. In contrast, the untreated mice showed grade one
(very light healing) of wound healing after 14th days of
operation with low collagen content, scarce vascularity or
low number of capillaries, absence of granulation tissue, no
abscess formation, no necrotic epithelium (Fig. 6). In addition,
histopathological examinations from the day 21st of wound
healing have showed grade 3 and 4 of wound healing in PRP
treated mice with abundant collagen fibers, capillaries, well
organized granulation tissue, comparing to control mice
where they showed grade 2 of wound healing with moderate
content of collagen and capillaries, onset of granulation tissue
formation (Fig. 6).
DISCUSSION
The results of this current study have shown that the skin
wound healing, by application of bovine fetal PRP, was
enhanced following 14 days of treatment with PRP comparing
to un-treated mice. Likewise, bovine fetal PRP produced a
potent wound healing effects at the end of experiments on
the 21st day of treatment as PRP application caused a
complete closure of the excised skin wound in treated mice,
comparing to un-treated mice. This effect could potentially be
through the influence of alpha granules in platelets that can
secret a wide range of growth factors which play an important
role in the process of soft tissue wound healing20,21. It is also
consistent with previous results which suggested that PRP has
been used in combination with stem cell therapy to augment
the tissue healing response18. Results of this study also
supported by previous works that showed human PRP plays
an important role in promoting of wound healing responses,
potentially through its fast and effective influence on
fibroblast proliferation, which are responsible for producing
most of the extracellular matrix tissue to enhance tissue repair
and wound healing22,23.
Furthermore, results of this study provided further insight
into the role of bovine PRP in promoting wound healing
process, because there was an obvious increase in the
percentage of wound closure following bovine PRP treatment
at 7th, 14th and 21st day post wounding in mice, comparing
to control mice without treatment. One potential explanation
for this apparent result could be that PRP can secrete
platelet-derived growth factor (PDGF), which stimulates the

24
 Int. J. Pharmacol., 16 (1): 18-26, 2020
production of fibronectin, a cell adhesion molecule, used in
cellular proliferation and migration during healing response
that accelerate soft-tissue healing through enhancement
of wound contraction and restoration. Another possible
explanation could be that PDGF derived from platelets play an
essential role in angiogenesis and neo-vascularization via
stimulating increased levels of vascular endothelial growth
factor at the site of wound, this leads to increase in wound
contraction and closure21. In addition, results of this study
were consistent with most recent works by Farghali
et al.24 and Pastar et al.25, who showed that direct application
of PPR on to the excised wound in dogs, for 3 sequential
weeks, caused obvious enhancement of re-epithelization and
wound contraction throughout the study period26.
Histopathological investigations of the healed wounds in
PRP treated mice showed obvious improvement in wound
healing especially after 14th and 21st day of skin wounding,
comparing to control mice without treatment. There was
higher collagen fibers, large numbers of capillaries
(angiogenesis), well organized granulation tissue formation in
PRP treated wound in time dependent manner comparing to
control group. Angiogenesis play a vital role to supply a
sufficient amount of oxygen and nutrients to the newly
formed granulating tissue in the wound. As soon as the
granulation tissue cot is arranged, the process of
re-epithelialization can take place23,26. The most likely
explanation would be that PRP contains copious amount of
growth factors such as transforming growth factor (TGF)-$,
which decreases the proliferation of basal keratinocyte whilst
persuades the differentiation of supra-basal cell, this leads to
stimulation of the epidermal regeneration associated with skin
wound healing27,28. In addition, increase in granulation tissue
formation and re-epithelization could be attributed to
significant increase in the activity and expression of matrix
metalloproteinase (MMP)-9 in PRP treated wound22 as MMP
plays an essential role in cell migration and re-epithelization
during skin wound healing24.
CONCLUSION
From the current data, it could be concluded that
application of bovine fetal PRP using topical and
subcutaneous infiltration route, simultaneously, at the
wound margins showed significant improvement in wound
re-epithelization and healing with reduced scar formation.
This route of PRP administration re-enforced the novel use of
the bovine fetal PRP as a biological wound healing enhancer.
Future experiments are needed to assess the effect o f PRP
on the skin tensile strength and elasticity after wounding,
through measuring the levels of collagen within the wound
25
via real-time PCR (qPCR) and immunohistochemistry
evaluation of COLIA2 gene expression in skin biopsies of PRP
treated and untreated wound in mice.
SIGNIFICANCE STATEMENT
This study discovered the potential effect of the fetal
plasma, which can be beneficial for the dermal wound healing
because of its positive influence on various phases of the
healing process. Recently, it has been documented that the
umbilical fetal plasma is effective in view of its content with
different types of growth factors that may help the tissue to
regenerate itself. Although, the mechanism of wound healing
has been delineated but its pathophysiological process is
still unclear and different materials were used in order to
enhance the process of wound healing. This study will help
the researcher to uncover the critical area of wound healing
therapy by using fetal plasma to improve the process of
wound healing and resolved impaired or non-healed wounds,
that many researchers were not able to explore using a recent
new therapeutic method to facilitate the process of wound
healing. Thus, a new theory on using fetal plasma is to design
an effective wound healing therapy protocol, which may be
arrived at if it supported by continuing with enormous
importance of researches in the future.
ACKNOWLEDGMENT
We would like to express the profound sense of gratitude
to all the doctors and technicians in the Histopathology
Department of Shorsh Hospital for their cooperation and
assistance, for their helpful assistance and generous support
during this research study. This research received no specific
grant from any funding agency in the public, commercial or
not-for-profit sectors.
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