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journal homepage: www.JournalofSurgicalResearch.com

Allogeneic Platelet-Rich Plasma Therapy as an

Effective and Safe Adjuvant Method for Chronic
Wounds

Xuan Liao, MD, PhD,a,1 Jun-Xian Liang, MD,a,1 Sheng-Hong Li, MD,a
Su Huang, MD,a Jian-Xin Yan, MD,a Li-Ling Xiao, MD,a
Jian-Xing Song, MD, PhD,b and Hong-Wei Liu, MD, PhDa,*
a
Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Innovative Technology Research
Institute of Tissue Repair and Regeneration, Key Laboratory of Regenerative Medicine, Ministry of Education,
Guangzhou, Guangdong, China
b
Department of Plastic Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China

article info abstract

Article history: Background: Platelet-rich plasma (PRP) improves the healing of refractory wounds, and its
Received 24 March 2019 application is receiving more attention in the field of wound repair. However, when a
Received in revised form patient’s condition is very poor, it may be difficult to provide whole blood to harvest
22 July 2019 autologous PRP.
Accepted 13 September 2019 Methods: We evaluated the efficacy and safety of allogeneic PRP in the field of chronic re-
Available online xxx fractory wound repair. Sixty patients (39 males and 21 females, 57
10 y old) with chronic
wounds were enrolled in this prospective, randomized, single-center study during January
Keywords: 2014 to January 2018. Their wounds were treated by standard care. The patients with
chronic wounds chronic refractory wounds were divided into allogeneic PRP treatment and control groups
allogeneic PRP on the basis of the presence or absence of allogeneic PRP in wounds after debridement,
wound healing respectively. Allogeneic PRP was prepared by collecting whole blood from healthy in-
dividuals and two-step centrifugation. Clinical effects were evaluated by visually observing
wound conditions and objectively assessing wound surfaces.
Results: After 30 d of treatment, the allogeneic PRP-treated group showed bright red gran-
ulation that bled easily with reduced inflammatory exudation. No rejection reactions were
observed. The rate of chronic wound healing was much faster in the allogeneic PRP-treated
group than that in the control group.
Conclusions: The present study shows that combined treatment of chronic wounds by
standard care and allogeneic PRP significantly shortens healing time, suggesting that
allogeneic PRP is an effective, safe adjuvant treatment for chronic wounds.
ª 2019 Elsevier Inc. All rights reserved.

* Corresponding author. Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Innovative Technology Research
Institute of Tissue Repair and Regeneration, Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, Guangdong,
510630, China. Tel.: þ86 20-386-88163; fax: þ86 20-3868-8446.
E-mail address: liuhongwei0521@hotmail.com (H.-W. Liu).
1
These authors contributed equally to this work.
0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jss.2019.09.019
 liao et al  allogeneic prp and chronic wounds 285

Table 1 e Characteristics of the study population.

Introduction
Parameters Control group PRP group
(%) (%)
Chronic refractory wounds are considered to be unhealed
wounds that last for more than 3 mo and are unable to restore Age (y)
anatomical and functional integrity through an orderly and 40-49 23 23
timely repair process.1 Regardless of developed or developing 50-59 50 20
countries, chronic refractory wounds are costly because of 60-69 17 33
their complicated etiology, prolonged disease duration, very
70-79 10 23
high treatment costs, consumption of medical resources, and
Gender
reduction of quality of life and work output, which are a major
Male 70 60
burden for society.2,3 Accordingly, promoting wound healing
in chronic refractory wounds, shortening the treatment Female 30 40
period, and reducing patient stress are the target of clinical Anatomical distribution
research. With the development of genetic engineering, tissue Back 10 7
engineering, and stem cell culture, the clinical application of Sacrococcygeal region 3 13
PRP which contains a large variety of growth factors that The lower part of the lower leg 20 17
promote wound healing in chronic refractory wounds has
Ankle 17 10
received increasing attention.
Foot 50 53
PRP is a concentrated platelet plasma obtained by sepa-
Nutritional condition
rating and concentrating whole blood, which has a concen-
tration of at least four times the platelets in whole blood.4 It Serum albumin ＞30 g/L 13 20

contains abundant growth factors5 and has a healing effect on Serum albumin 30 g/L 87 80
wounds and tissues.6 The increasing maturation of separation Etiology
and extraction technologies for PRP has led to a simple and Burns 13 23
rapid operation, which is not easily contaminated and has a Diabetic foot 23 30
reliable curative effect. Therefore, the use of PRP to promote
Venous ulcer 30 23
chronic refractory wound healing has become a research
Pressure ulcer 30 17
focus. However, patients often have severe underlying dis-
Immune diseases 3 7
eases or are elderly and their conditions do not meet the re-
quirements of extracting PRP to ensure quality and quantity.
Considering the urgent need for disease treatment, the use of
allogeneic PRP will effectively solve this limitation.
Methods

Patients and methods Source of allogeneic PRP

Patients
Sixty patients with chronic wounds were treated at our
department from January 2014 to January 2018. Their average
age was 57
10 y and 60% were women. The treatment was
used for chronic wounds with a mean ulcer area of 33.6 cm2,
which had been treated for more than 6 mo. Refractory wound
occurred in various parts of the body, including five cases in
the back, five cases in the sacrococcygeal region, five cases of
the right lower limb, six cases in the lower part of the left
lower leg, five cases in the right ankle, and three cases in the
left ankle. In addition, wounds in 17 cases occurred on the
dorsal side of the left foot and wounds in 14 cases occurred on
the dorsal side of the right foot. The patients with chronic
refractory wounds were randomly and equally assigned to
two groups. Thirty patients were treated with debridement
and allogeneic PRP in the treatment group, and the other pa-
tients were treated by conventional wound-cleaning methods
in the control group. According to the wound condition, both
groups underwent skin grafting to accelerate wound healing.
The study was approved by the ethics committee of the first
affiliated hospital of Jinan university. Informed written con-
sent was obtained from all patients (Table 1).
Allogenic PRP was derived from the peripheral blood of im-
mediate family members of the patient, and its serological test
indicators met the Chinese blood donation requirements.
Human immunodeficiency virus, HbsAg, hepatitis C virus, and
syphilis serum reaction tests were negative. Males were aged
less than 55 y, and females were aged less than 50 y. The donor
record and blood acquisition registration form were obtained
at the time of blood collection, together with the donor serum
test results for follow-up.
PRP preparation
PRP was isolated from the blood using a previously described
procedure.7 Briefly, we performed secondary centrifugation
for extraction. First, 60 mL venous blood was collected in a
sodium citrate anticoagulated centrifuge tube. After centri-
fugation at 400g for 10 min, the blood was divided into three
layers, the uppermost layer was platelet-poor plasma (PPP),
the red blood cell layer was at the bottom, and the platelet-
rich plasma was the middle layer. The uppermost superna-
tant layer which PPP was aspirated with a Pasteur pipette and
the intermediate layer to a distance of 2 mm from the bottom
286 j o u r n a l o f s u r g i c a l r e s e a r c h  f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 8 4 e2 9 1

layer were pipetted out. Then, the collected layer was centri- infection, frequency of dressing replacement, immediate
fuged at 1200 g for 20 min, and the liquid was separated into adhesion of grafts, graft edema after transplantation, skin
two layers after centrifugation. The sediment was collected as graft survival, healing time, and wound healing rate.
PRP. For clinical treatment, the platelets were activated by
calcium gluconate at a ratio of 10:1, and the wound was
Statistical method
treated within 10 min to avoid gel formation. The operation
was performed with strict sterility, and PRP was used imme-
SPSS 16.0 software was used for statistical analysis. An inde-
diately after each extraction.
pendent sample t-test was used to calculate the difference
between the two groups.
Platelet count assay

After PRP preparation, 0.5 mL was collected within 30 min and

placed in a blood cell analyzer with an equal amount of
venous blood to measure the platelet count. Platelet concen-
tration values were compared between whole blood and PRP
to ensure that the platelet count in PRP was greater than four
times the platelet count of whole blood.
Clinical therapy
Hydrogen peroxide, chlorhexidine, and normal saline were
used to thoroughly clean the wound surface, and the purulent
secretion and necrotic tissue of the wound were cleaned off
with a blade to expose the healthy tissue. After cleansing, the
wound was washed again with normal saline and dried with
sterile gauze. The use of therapeutic agents containing basic
fibroblast growth factor was prohibited during the PRP injec-
tion study period. Moreover, negative pressure wound therapy
was also banned during the PRP study. After the completion of
the PRP clinical injection study, no restrictions were imposed.
The prepared allogeneic PRP was evenly injected into the
wound surface, and the wound surface was wet-coated with a
PPP wet gauze and finally dressed. Wound healing was
observed every other day, and the wound dressing was
changed. After the wound granulation became fresh, it was
covered with a skin graft.
Safety evaluation of allogeneic PRP application
Before and after treatments, blood samples were tested for
transfusion-related infectious diseases, human leukocyte an-
tigen, and antiplatelet antibodies. Wounds were observed for
abnormalities such as worsening, increased infection, local
tissue hyperplasia, and poor wound healing. These observa-
tions are used to assess the safety of allogeneic PRP therapy.
Results
Platelet measurements
After platelet count, the amount in venous blood was 100-
300  109/L, and the average was 200
49  109/L. The average
platelet count in PRP prepared by the two-step centrifugation
was 1200
137  109/L, which was four to seven times
compared with the average platelet count in total venous
blood. High magnification showed a significant increase in
platelets of PRP (Fig. 1).
Clinical efficacy and healing rate analysis
All patients who underwent allogeneic PRP injections were
not found to have a treatment-related adverse reaction during
the study period. Patients who underwent allogeneic PRP
wound treatment were followed up after the first injection
into the wound bed. In 30 patients, necrotic tissue and pus had
mostly disappeared, granulation tissue was fresh, and the
color was rose red. Thirty patients had good outcome, and the
wound healing rate was 100%. The follow-up period was 6 mo
to 4 y, during which no recurrence of ulcers was found. The
most relevant cases are presented in Table 2. The data showed
that there was a significant difference in the rate of chronic
refractory wound healing between the control and experi-
mental groups in the first and third weeks (first week:
t ¼ 7.6349, P < 0.05; third week: t ¼ 18.456, P < 0.05).

Calculation of the wound healing rate

The chronic refractory wound healing rate was used to assess

wound healing as the most appropriate indicator of this pro-
cess. The wounds in each group were photographed on day 7.
The wound healing rate was calculated by the following
formula:
Wound healing rate (%) ¼ ([the original wound size 
wound size]/[the original wound size])  100.

Objective parameters to assess the efficacy of PRP Fig. 1 e Platelet count in PRP and whole blood assessed by
the blood cell analyzer. Values are expressed as
We selected the following parameters to evaluate the efficacy means ± SEM of three independent experiments. *P < 0.05
of PRP, such as granulation growth of wounds, presence of versus control.
 liao et al  allogeneic prp and chronic wounds 287

Table 2 e Review of patients’ treatment.

Wound area Time Experience group Control group

Wound area Healing rate (%) Wound area Healing rate (%)
Back On admission 49.3
4.5 - 56.5
2.1 -
After 1 wk of treatment 26.3
1.5 46.4 44.0
5.7 21.9
After 3 wk of treatment 5.7
0.6 88.5 36.5
4.9 35.2
Sacrococcygeal region On admission 59.0
0.0 - 64.8
3.8 -
After 1 wk of treatment 28.0
0.0 52.5 53.0
3.6 18.2
After 3 wk of treatment 7.0
0.0 88.1 42.2
1.7 34.6
The lower part of the lower leg On admission 95.3
12.0 - 85.8
8.6 -
After 1 wk of treatment 48.7
3.1 48.5 76.4
4.0 10.5
After 3 wk of treatment 10.2
1.5 89.2 61.8
2.6 27.5
Ankle On admission 10.8
2.2 - 11.3
1.5 -
After 1 wk of treatment 5.0
0.0 52.3 8.3
0.6 26.0
After 3 wk of treatment 0.2
0.4 98.6 5.3
1.2 53.1
Foot On admission 11.8
2.4 - 10.7
2.4 -
After 1 wk of treatment 5.4
1.6 52.8 7.3
1.4 28.3
After 3 wk of treatment 0.7
0.9 92.9 5.8
1.2 44.0

Case presentation Patient 3 was a 77-year-old male with 30 y of type 2 dia-

Patient 1 was a 63-year-old man with a history of 20-y of type 2
diabetes, accompanied by known macrovascular and micro-
vascular complications, who has had a nonhealing diabetic
foot ulcer for up to 1 y. The right foot was obviously cyanotic,
the first to third toes were black, showing dry necrosis, and the
fourth toe was partially seen with an ulcer and variegated
changes with purulent exudation. The skin of both feet was
low, and the bilateral femoral, dorsal, and posterior tibial ar-
teries were not accessible. The patient was diagnosed as lower
extremity arterial occlusion and diabetic foot necrosis of
Wagner grade 4.8 After admission, vascular treatment was
performed to open the lower extremity vascular. The wound
was thoroughly cleaned with hydrogen peroxide, and then the
wound purulent exudate and necrotic tissue were removed.
After debridement, 50 mL whole blood from a family member
was collected to prepare 5 mL PRP that was activated by a 10:1
ratio of calcium gluconate and uniformly injected into the
wound. After daily changes of the wound dressing for 1 wk,
the wound was fresh and rose red, and a skin graft was used
for treatment. The chronic refractory wound recovered well.
Wound healing was good during the follow-up period (Fig. 2).
Patient 2 was a 60-year-old male with a right lower ex-
tremity chronic skin ulcer for 7 y due to venous hypertension.
The ulcer measured 12.0  9.5 cm2. Purulent secretions were
attached to the upper part, and pigmentation was visible
around the infection. After full debridement, the fresh wound
was uniformly injected with PRP after activation by calcium
gluconate, and the skin from the outside of the thigh was
transplanted to the wound. The wound was basically covered
by the growth of the skin after 3 wk of the thin-split-thickness
skin grafting. Allogeneic PRP injection combined with thin
skin grafting had a smooth course and no complication, and
patient had persistent wound coverage within 12 mo after
surgery (Fig. 3).
betes, who presented with a 6-mo history of a nonhealing skin
chronic ulcer caused by a burn injury on the outside of the left
calf. The ulcer measured 4  3 cm2, there was invasive edema
around the wound surface, the center of the wound had
ruptured, and there was more purulent exudates. After thor-
oughly cleaning the wound with hydrogen peroxide, saline,
and chlorhexidine to remove purulent exudate and necrotic
tissue from the wound, debridement and then allogeneic PRP
activated by calcium gluconate were applied on wound beds.
A skin graft was then used for treatment, and the wound
recovered well after 1 wk. The grafted skin survived without
abnormal exudation. After a 1-y follow-up after discharge, the
wounded skin had recovered well (Fig. 4).
Discussion
A refractory wound involves normal healing under the influ-
ence of various internal and external factors, which makes the
wound surface heal for a long time and has a tendency of
gradually expanding. Particularly in diabetic patients and the
lower tibia, ankle, and other parts, difficult to treat wounds are
particularly common, and their anatomical structure is
unique such as less subcutaneous soft tissue and a poor blood
supply. Therefore, once these areas undergo ulceration, the
wound does not heal easily.9 With aging of the population,
chronic diseases such as diabetes and hypertension have
increased. These chronic diseases aggravate arteriosclerosis
and excessive blood sugar that are also not conducive for
wound healing. Under the treatment of conventional
debridement and dressing, the curative effect is poor. A re-
fractory wound has a heavy psychological and economic
burden on patients and their families because of the pro-
longed course of the disease, which causes many patients to
interrupt their treatment, thereby further aggravating the
288 j o u r n a l o f s u r g i c a l r e s e a r c h  f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 8 4 e2 9 1
Fig. 2 e Patient 1. (A) Lower extremity arterial occlusion and diabetic foot necrosis, Wagner grade 4. (B) After vascular
treatment and debridement, the wound bed was injected with activated PRP. (C) At 1 wk after the skin graft, the skin had
survived well. (D) Durable wound coverage after 12 mo.
condition. Therefore, chronic refractory wounds have become
a major problem in the clinic.
PRP is a concentrated platelet plasma obtained by sepa-
rating and concentrating venous blood, which is activated by
calcium to release a large amount of growth factors which has
a good effect on tissue repair. Addition of calcium ions to
activate PRP causes gradual formation of a colloidal shape,
which effectively delays the loss of platelets on the wound
surface, so that the large amount of platelets contained in PRP
has the ability to continuously secrete growth factors and
synthesize functional proteins, including vascular endothelial
growth factor, platelet-derived growth factor, and epidermal
growth factor, to promote wound repair. Because the con-
centration of platelets in the isolated and purified PRP is much
high than the conventional physiological concentration, it is
currently recognized that the effective therapeutic concen-
tration of PRP is three to six times higher than the physio-
logical concentration.10 There is no uniform standard for PRP
preparation, and the principle lies in the difference in the
proportion of blood components. Thus, PRP containing a high
concentration of platelets is desirable. Using different prepa-
ration methods, the release of the growth factor content is not
the same, and the quality and quantity of PRP are affected by
many factors such as the centrifugal force and time. Under the
PRP separation conditions in this study, the concentrations of
PRP isolated for clinical treatment were more than four times
the physiological concentration. The concentration of isolated
and purified platelets in PRP determines the amount of
various growth factors. The surfaces of platelets themselves
can be used as a biological scaffold to provide attachment for
growth factors and accumulation of chemotactic cells.11,12
The growth factors of highly concentrated platelets can
compensate for the lack of growth factors’ quantity in chronic
refractory wounds. The concentrations of epidermal growth
factor, transforming growth factoreb, vascular endothelial
growth factor, and platelet-derived growth factor are higher
than those of normal growth factors in vivo,13 thus promoting
the proliferative capacity and migration ability of wound
repairerelated cells such as keratinocytes, fibroblasts, osteo-
blasts, and vascular endothelial cells.14-20 In addition, plate-
lets participate in the inflammatory response and anti-
inflammatory immunity of the host as a specialized “white
blood cell” and participate in the process of tissue repair.21-23
Similarly, after platelets are activated, fibrinogen in plasma
is converted to fibrin that promotes activation of the coagu-
lation function of the wound, which contracts the wound
surface and provides a three-dimensional support space for
the proliferation of wound-related cells.
With the deepening of PRP research, PRP has been widely
used in burn orthopedics, orthopedics, chronic ulcers, and
oral and maxillofacial surgeries.24 Moreover, it has been re-
ported that combination of PRP with adipose-derived stem
cells or stromal vascular fraction cells improved the healing of
chronic skin ulcers.25,26 It has been confirmed that PRP
 liao et al  allogeneic prp and chronic wounds 289

Fig. 3 e Patient 2. (A) Chronic venous lower leg ulcer for 7 y refractory to multiple conventional skin grafts. (B) After repeated
debridements, the wound bed was injected with activated PRP. (C) At 3 d after a skin graft, the thin-split-thickness skin graft
had survived. (D) Durable wound coverage after 12 mo.

treatment significantly shortens the operation time and re-
duces postoperative pain and swelling. The most important
factor is the promoting effect on wound healing. However, the
application of autologous PRP also has certain limitations.
From the patient’s perspective, mostly middle-aged and
elderly patients have chronic refractory wounds, and most of
them are associated with chronic diseases such as hyperten-
sion and diabetes. Their conditions are poor, and their blood
platelet function hardly achieves the expected therapeutic
effect of PRP. Furthermore, PRP treatment requires 50-100 mL
of blood extraction per patient, which is likely to aggravate the
physical burden on patients with poor general conditions.
Because of the limitations of PRP collection conditions, prep-
aration techniques, and environmental requirements, the
popularization and application of autologous PRP have
encountered great obstacles.
In this regard, we believe that patients cannot provide PRP
for wound treatment because of their own limitations, and the
use of allogeneic PRP will effectively solve this limitation. PRP
has low immunogenicity for allogeneic use. In this study, 30
patients who underwent allogeneic PRP treatment achieved
good results, and no immune response occurred during the
procedure. As early as 2003, Carter et al. applied homologous
PRP to a male horse refractory wound model, and found high
density and largely ordered collagen bundles at 79 d.27 How-
ever, there was only a small amount of disordered collagen
fibers in the wounds of the control group. This study
confirmed that allogeneic PRP had the same therapeutic effect
on chronic wounds, and no abnormal side effects were found
during the experiment. Smrke et al. used a human thrombin-
activated, homologous platelet-derived platelet gel mixed
autologous bone cancellous graft to treat delayed fracture
healing of a diabetic comminuted fracture. After 6 mo, the
patient’s tibia had healed, the bone defect was completely
bridged, and the load was normal. There were no abnormal
side effects during the entire clinical treatment period, and no
antiplatelet antibodies or anti-HIA-I antibodies were found.28
A study by Han et al. showed that PRP prepared using stock
platelets promotes healing of diabetic wound models.29
Compared with autologous PRP, allogeneic PRP has a wide
range of sources and is easy to collect. PRP can even be pre-
pared at blood collection institutions, and high-quality plate-
lets can be screened to further ensure the efficacy and
application of PRP technology.
290 j o u r n a l o f s u r g i c a l r e s e a r c h  f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 8 4 e2 9 1
Fig. 4 e Patient 3. (A) Chronic lower leg burn ulcer for 6 mo. (B) The wound bed was injected with activated PRP immediately
after debridement. (C) At 1 wk after the skin graft, the skin survived well. (D) Durable wound coverage after 12 mo.
Clinical application of allogeneic PRP to the treatment of
chronic wounds should consider to the following aspects.
First, allogeneic PRP from donor blood must undergo strict
testing to avoid the spread of blood-borne diseases. Second,
the PRP extraction process must comply with operating rules
and adhere to the principle of sterility, while ensuring the
platelet concentration in PRP. For the treatment of wounds, it
is necessary to control the patient’s chronic diseases. When
faced with a large area refractory wound and poor blood
supply to the wound surface, it may be better to combine
debridement, vacuum suction, and wound skin grafting. If the
wound is accompanied by a suppurative infection, PRP should
be applied after thorough debridement of the infection.
In summary, we studied cases of allogeneic PRP treatment
of chronic refractory wounds, achieved significant results, and
observed no adverse reactions. Therefore, patients with
chronic refractory wounds, who have generally poor condi-
tions or other chronic underlying diseases, may choose to be
treated with allogeneic PRP.
Acknowledgment
This work was supported by the National Nature and Science
Foundation, China (81372065 and 81871563), the Major Project
of Guangzhou Municipal Science and Technology Bureau
(201300000091 and 201508020253), the Fundamental Research
Funds for the Central Universities (21619350), and the foster
research fund of The First Affiliated Hospital of Jinan Univer-
sity (No. 2017306).
The written informed consent of this study was obtained
from each individual.
All procedures performed in studies involving human
participants were in accordance with the ethical standards of
the institutional and/or national research committee and with
the 1964 Helsinki declaration and its later amendments or
comparable ethical standards.
Authors’ contributions: X.L. and J-X.L. contributed to
conception and design, collection and/or assembly of data,
data analysis and interpretation, manuscript writing, and
provided study material. S-H.L. provided study material and
contributed to collection and/or assembly of data. S.H. pro-
vided study material and contributed to collection and/or as-
sembly of data, data analysis, and interpretation. J-X.Y.
contributed to collection and/or assembly of data, data anal-
ysis, and interpretation. L-L.X. provided study material and
contributed to collection and/or assembly of data. J-X.S.
contributed to conception and design, data analysis and
interpretation, and provided administrative support. H-W.L.
contributed to conception and design, data analysis and
interpretation, final approval of the manuscript and provided
financial support and administrative support.
Disclosure
No competing financial interests exist.
 liao et al  allogeneic prp and chronic wounds
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