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 Growth Factors, April 2010; 28(2): 111–116

Evidence on the use of platelet-rich plasma for diabetic ulcer:

A systematic review

DIANA LIMA VILLELA1 & VERA LÚCIA C. G. SANTOS2

1
Department of Continuing Education, A. C. Camargo Cancer Hospital, São Paulo, Brazil, and 2Nursing School, University of
São Paulo/EEUSP-SP, São Paulo, Brazil
Growth Factors Downloaded from informahealthcare.com by Novartis Knowledge Center on 08/08/10

(Received 20 July 2009; accepted 5 November 2009)

Abstract
The aim of topical wound treatment is to favor efficient, rapid, and safe healing. The platelet-rich plasma (PRP) has been used
for wound treatment since it contains various platelet growth factors. The objective of the present study was to collect evidence
regarding the use of PRP for the topical treatment of chronic leg ulcers. For this purpose, a systematic review of the literature
was performed according to the steps recommended by the Cochrane Collaboration with studies published until July 2008.
Among 18 selected studies, 7 (39%) of these studies were randomized clinical. Five of the seven randomized clinical
trials studied ulcers of diabetic etiology. The results of meta-analysis showed that PRP favors the healing process (95% CI:
For personal use only.

2.94 – 20.31). In conclusion, the present systematic review and meta-analysis show that there is a scientific evidence regarding
favorable outcomes of the use of PRP for the treatment of diabetic ulcer.

Keywords: Platelet-rich plasma, wound healing, diabetic ulcer

Introduction
Wound healing is a dynamic process that involves
complex mechanisms mediated by different growth
factors (Ma et al. 2007). These growth factors can be
isolated at high concentrations from platelet-rich
plasma (PRP), an emerging tool in tissue engineering
therapies and a subject of investigation on the part of
clinicians and researchers (van den Dolder et al.
2006). Studies on the restoration of tissue integrity
have demonstrated platelet activity along the healing
process from coagulation to the inflammatory phase,
mediating blood clot formation by the induction of
adhesion, aggregation, and degranulation of circulat-
ing platelets (Crovetti et al. 2004). Platelet a-granules
store different growth factors such as platelet-derived
growth factor (PDGF), epidermal growth factor,
fibroblast growth factor, transforming growth factor,
insulin-like growth factor, and vascular endothelial
growth factor (Dvorak et al. 1995; Singer and Clark
1999; Crovetti et al. 2004; Everts et al. 2006; van den
Dolder et al. 2006; Ma et al. 2007).
Understanding wound healing as an endogenous
process does not imply disregarding topical treatment.
However, one cannot exclusively attribute to dressing
functions that do not belong to it. Healing is a
systemic process but topical wound care is a factor
that may contribute to or impair the work of the
organism (Meneghin and Vatimo 2003).
PRP, which contains different growth factors, is one
of the substances available for topical wound treat-
ment. Defined as a hemocomponent, PRP is obtained
from the combination of high concentration of
platelets and cryoprecipitates, permitting an
additional supply of growth factors during the healing
process (Marx 2001; Crovetti et al. 2004).
The use of growth factors for the topical treatment
of chronic wounds is based on the fact that these
factors are reduced in the wound bed during this
phase. Growth factors are found throughout the

Correspondence: D. L. Villela, Department of Continuing Education, A. C. Camargo Cancer Hospital, São Paulo, Brazil. Tel: 55 11 29721039.
Fax: 55 11 21895050. E-mail: diana.villela@hcancer.org.br

ISSN 0897-7194 print/ISSN 1029-2292 online q 2010 Informa UK Ltd.

DOI: 10.3109/08977190903468185
 112 D. L. Villela & V. L. C. G. Santos
healing process and their contribution to topical
wound healing has been demonstrated over the last
decade. In future, growth factors will probably no
longer be applied in combination but rather a single
factor will be used for each phase of the healing
process (Schultz et al. 2003).
In view of the recent introduction of PRP in Brazil,
the objective of the present study was to review the
scientific evidence regarding the results of the use of
PRP for the topical treatment of chronic leg ulcers.
Methods
A systematic review of the literature was performed
according to the procedures adopted by the Cochrane
Growth Factors Downloaded from informahealthcare.com by Novartis Knowledge Center on 08/08/10
Collaboration. Included in the study were research
articles on the use of PRP for the treatment of chronic
leg ulcers in humans, published and indexed in the
Cochrane, Lilacs, Cinahl, Embase, and PubMed
databases until July 2008. The following criteria were
established for the selection and inclusion of articles:
clinical trials, complete articles, and articles published
in international and national journals indexed in the
databases mentioned above. Exclusion criteria were
articles, editorials and letters published in abstract
form, studies using platelet-poor plasma in combi-
For personal use only.
nation with PRP, and studies using a recombinant or
single growth factor.
The following keywords indexed in the MeSH and
DeCS databases were used for the search: wound
healing, diabetic foot, varicose ulcer, foot ulcer,
PDGF, CT-102-activated platelet supernatant, and
PRP. Some non-indexed keywords were also used:
platelet releasate, platelet lysate, platelet gel, chronic
wound, and diabetic ulcer. These keywords were
grouped in different manners according to the PICO
electronic search method proposed by Nobre et al.
(2004a, b): P ¼ population, I ¼ intervention, C ¼
comparison, and O ¼ outcome. After reading some
articles, we observed that some of them used wound
healing or chronic wound as keywords. To avoid limiting
the retrieval of studies, keyword crossing was
performed using wound healing OR chronic wound
and not wound healing AND chronic wound as originally
proposed by the PICO strategy.
Data were collected in the first half of 2008 by
an electronic search (Internet) of the previously
established databases. After the complete articles
had been accessed, the following data were collected
using a specific instrument: name of the authors,
country of origin, type of study, sample, method used,
time of contact of PRP with the wound, and PRP
concentration. The electronic search was performed
on each of the five databases selected. All studies
retrieved by the search strategy were evaluated
regarding title and abstract. In order to avoid
erroneous exclusions, the studies were included in a
preselection even in cases in which the data provided
were not sufficient. After the complete articles were
obtained, their references were also analyzed in order
to retrieve possibly still unidentified studies.
Data analysis
The data were analyzed in four phases:
Characterization of the selection process of the studies
(phase 1). Analysis of the total number of studies
retrieved per database and of studies included in the
review, as well as evaluation of the characteristics of
the journals in which the studies were published.
Characterization of the studies included (phase 2).
Analysis of the study data according to type of
research, variables controlled during the healing
process, characterization of PRP (collection method
and concentration), and dressing techniques used.
Evaluation of the quality and evidence of the studies
included (phase 3). The studies were evaluated
regarding their quality (internal validity) using the
following scales: (1) A scale for the assessment of grade
of recommendation and level of evidence (SGRLE) as
proposed by Nobre and Bernardo (2006), where grade
A ¼ strong recommendation, grade B ¼ moderate
recommendation, and grade C/D ¼ low recommen-
dation. (2) A scale for the assessment of the control of
variables (SACV). Although no standardized scale
exists for the assessment of intrinsic and extrinsic
variables that interfere with chronic wound healing, for
the present study a scale was elaborated surveying all
variables controlled by the authors of the studies
included in the systematic review. Since, only eight
variables were identified, including five intrinsic (age,
etiology, associated disease, ulcer duration and infec-
tion) and three extrinsic variables (type of previous
treatment, multiprofessional treatment, caregiver), a
dichotomous classification was adopted, i.e. controlled,
including studies that analyzed 7 –8 variables, and non-
controlled, including studies that analyzed 0– 6 vari-
ables, irrespective of the type of variable. (3) Jadad scale
(Jadad et al. 1996), which was only applied to
randomized controlled clinical trials.
In order to improve the analysis of the quality of the
clinical trials included, a combination of the SGRLE
and SACV scales was used based on the model of the
Oxford Centre for Evidence-Based Medicine and also
adapted by Nobre and Bernardo (2006) as shown in
Table I.
Statistical analysis (phase 4). After analysis of the
randomized clinical trials included in the systematic
review, those with a score of three points or higher on
the Jadad scale (considered to be methodologically
similar), those that treated diabetic ulcers, were
submitted to a meta-analysis. Meta-analysis was
performed in three steps according to the classification
of the results into homogenous (fixed effect) or
heterogenous (random effect). In addition, since two
of the four randomized trials were similar in terms of
 Evidence on the use of platelet-rich plasma 113

Table I. Scale for the assessment of the grade of recommendation and level of evidence associated with the scale for the assessment and
control of variables.

Grade of Level of
recommendation evidence Study

A A1þ Systematic review (with homogeneity) of randomized controlled clinical trials, with analysis of the
interfering variables proposed
A12 Systematic review (with homogeneity) of randomized controlled clinical trials, without analysis of the
interfering variables proposed
A2þ Randomized controlled clinical trial (with a CI), with analysis of the interfering variables proposed
A22 Randomized controlled clinical trial (with a CI), without analysis of the interfering variables proposed
A3þ All or none outcome research, with analysis of all interfering variables proposed
A32 All or none outcome research, without analysis of all interfering variables proposed
B B1þ Systematic review (with homogeneity) of cohort studies, with analysis of the interfering variables proposed
B12 Systematic review (with homogeneity) of cohort studies, without analysis of the interfering
variables proposed
B2þ Cohort study (including poor quality randomized clinical trials), with analysis of the interfering
Growth Factors Downloaded from informahealthcare.com by Novartis Knowledge Center on 08/08/10

variables proposed
B22 Cohort study (including poor quality randomized clinical trials), without analysis of the interfering
variables proposed
B3þ Outcome research and ecological study, with analysis of the interfering variables proposed
B32 Outcome research and ecological study, without analysis of the interfering variables proposed
B4þ Systematic review (with homogeneity) of case-control studies, with analysis of the interfering
variables proposed
B42 Systematic review (with homogeneity) of case-control studies, without analysis of the interfering
variables proposed
C Case series (including poor quality cohort or case-control studies), with analysis of the interfering
variables proposed
D Expert opinion without critical appraisal based on consensus and physiological studies using biological
material or animal models
For personal use only.

the method of collection and type of PRP used (CT- with 3830 patients. No control group was present in
102), they were also submitted to meta-analysis studies S15, S30, S34, and S52.
assuming again a random effect. The following variables were mentioned in all
studies: associated diseases, ulcer duration, and
etiology of chronic ulcer. Only in studies S25, S31,
Results and S36 did the authors control for all variables. The
type of previous topical treatment was the least
Many studies were present in more than one of the
controlled variable and was mentioned in only six
electronic databases and some studies were cited more
studies (S25, S30, S31, S36, S39, and S49).
than once in the same database. Among the 45,781
articles retrieved (PubMed: 72.8%, Cinahl: 8.4%, Table II. Distribution of the studies according to author, origin,
Embase: 17.8%, Lilacs: 0.6%, and Cochrane: 0.8%), and year of publication.
56 were preselected because they were clinical trials
S Main author Origin Year
and were related to the specific question of investi-
gation. Only three of the preselected articles were 06 Driver Russia 2006
narrative reviews of the subject. 13 Saldalamacchia Italia 2004
After reading and analyzing the complete prese- 14 Mazzucco Italia 2004
15 Crovetti Italia 2004
lected studies, doubtful articles in terms of the 25 Stacy Australia 2000
inclusion criteria were analyzed separately by two 29 Knighton EUA 1990a
reviewers who excluded 37 studies. The definitive 30 Ganio EUA 1993
sample of studies included in the systematic review 31 Margolis EUA 2001
thus consisted of 18 articles, which are shown in 32 Krupski EUA 1991
34 Knighton EUA 1986
Table II. 36 Doucette EUA 1989
Seven (39%) of the eighteen studies analyzed were 39 McAleer EUA 2006
randomized clinical trials (S6, S13, S25, S29, S32, 44 Keyser EUA 1993
S50, and S55). Cross-sectional clinical studies 47 Glover EUA 1997
appeared in second place, with three studies (17%). 49 Atri India 1990
50 Holloway EUA 1993
Two studies involved large samples: S31, a multi- 52 Knighton EUA 1990b
center retrospective cohort study with 26,599 55 Steed EUA 1995
patients, and S47, a multicenter case-control study
 114 D. L. Villela & V. L. C. G. Santos

With respect to the method of PRP collection, the Table IV. Confidence interval (95% CI) of the outcomes of the
studies S29, S30, S36, and S44 mentioned the studies.
method described in S34. In the other studies, PRP Control
the blood volume used ranged from 20 to 240 ml
and was obtained by centrifugation or apheresis. Study Healed Treated Healed Treated CI (95%)
The seven randomized clinical trials were evaluated S6 13 19 9 21 0.78–10.57
regarding their quality based on the three scales S55 5 7 1 6 0.83–186.29
described and regarding the proposed outcome S50 12 15 6 21 2.05–48.55
(Table III). (0,01)
E29 17 21 2 13 3.64–150.02
With respect to scientific quality, studies S6 and Total 47 62 18 61 2.94–20.31
S29, presented strong evidence according to the Jadad
scale, were strongly recommended by the SACV, and
positive results were reported with the use of PRP made a meta-analysis with them whose showed a
when compared to the respective control groups. In significant effect (95% CI: 2.70 – 41.40).
contrast, S25 and S32 reported no positive outcomes
Growth Factors Downloaded from informahealthcare.com by Novartis Knowledge Center on 08/08/10

with the use of PRP and were also classified as strongly

recommended.
Five studies from these seven randomized clinical
trials treated diabetic ulcers, but only four were
considered to be methodologically similar. On the
basis of the criteria established, a meta-analysis of
these four studies was performed using the data
described in Table IV.
Studies S50 (0.01) and S29 reported the best
outcomes for the treatment group, with 80 and 81% of
For personal use only.
Discussion
According to centers for evidence-based medicine,
randomized clinical trials are the most appropriate
type of study to provide adequate scientific evidence
for clinical practice. Nevertheless, these studies
require the assessment of their quality in terms
of certain conditions, such as process and type of
randomization, type of blinding, type and quantity
of losses during the experiment, and control of

healed wounds, respectively. No significant differ- variables, in order to generate recommendations for
ences between the control and treatment groups were clinical practice once at least their internal validity has
reported in studies S06 (0.1) and S55. been confirmed.
Among the 62 wounds treated with PRP, 47 The S29 was published by Knighton et al. in 1990.
(75.8%) healed faster than those not treated with This group was the first to report the use of growth
factors for wound treatment. In 1982, the authors
PRP (N ¼ 15, 24.2%). In the control group, 43
published an experimental study on rabbits
(70.5%) of the 61 wounds followed up did not heal.
using platelet-derived wound healing formula
Assuming heterogeneity, meta-analysis of the
(PDWHF) for the treatment of ocular lesions
studies yielded a 95% confidence interval (CI) of
2.94 –20.31. S50 (0.01) and S29 were the only studies
in which the CI did not overlap the vertical line at 1,
indicating a significant effect in favor of healing. In the
other studies, the CI reached level 1, i.e. no significant
effect was observed. When the studies were grouped,
meta-analysis showed that the trend toward the
occurrence of healing continued to be higher in the
PRP group compared to the control group, even when
assuming a random effect (Figure 1). The S55 and
S50 treated the wound with PRP as CT-102, so it was

Table III. Distribution of the studies according to quality

assessment.

Level of Favorable
Study evidence SACV Jadad to PRP

S6 1b A2 þ 5 Yes
S13 1b A2 2 3 Yes
S25 1b A2 þ 4 No
S29 1b A2 þ 5 Yes
S32 1b A2 þ 4 No
S50 1b A2 2 4 Yes
S55 1b A2 þ 3 Yes Figure 1. Meta-analysis graph based on the assumption of a
random effect.

(Knighton et al. 1986). Subsequently, in 1986, these
authors conducted an uncontrolled clinical trial (S34)
now using PDWHF for the treatment of nonhealing
chronic wounds. PRP was obtained by centrifugation
of 60 ml of blood and microcrystalline collagen was
added. Since, this was the first study to report the use
of PRP for wound treatment, some authors (S30 and
S44) have used the same method in their studies. Four
years later, the same group published “the first
evidence of a local action of growth factors promoting
the healing of nonhealing wounds in a randomized
clinical trial”, according to the authors themselves.
This statement was confirmed in the present
systematic review, since that study (S29) was classified
as strongly recommended. Within the limitations of
Growth Factors Downloaded from informahealthcare.com by Novartis Knowledge Center on 08/08/10
that study, the authors recognized that the sample was
small and that the groups had not been stratified
before randomization, although refined statistical
analysis showed that these factors did not interfere
with the conclusions of the trial.
Another fundamental aspect of the design of the
studies, in addition to quality, is related to the size of
the sample. The sample size of the studies analyzed in
this systematic review was small. Depending on the
subject of investigation—as in the case of chronic
wounds—it is not always easy to simultaneously
For personal use only.
conduct studies at different centers due to reasons
such as the characteristics of the target population,
teams, services, and treatments.
Unfortunately, even after analysis of the studies
included in this systematic review, it is practically
impossible to establish a reference value of the platelet
concentration in PRP necessary to produce healing.
Each study reported different methods and concen-
trations. Steed et al. (1992) (S55) and Holloway et al.
(1993) (S50) used PRP such as CT-102. In S50, the
authors studied three different concentrations of PRP
(0.01, 0.033, and 0.1), but only in the case of the
1:100 dilution (0.01) did they describe how the
dilution was done. No significant differences were
observed between the control (placebo) group and the
group treated with concentrations of 0.1 or 0.033,
whereas a significant difference was found for the
group treated with a concentration of 0.01, indicating
favorable outcomes of CT-102 ( p ¼ 0.01). In S55, the
authors randomized patients with diabetic foot ulcers
into a group treated with CT-102 at a concentration of
0.01 and a placebo group, and favorable outcomes
were also reported for the treatment group ( p , 0.05).
The results of these two studies show that the platelet
concentration used influences the healing process.
In a more recent study, Driver et al. (2006) (S6)
have also obtained favorable outcomes with the use of
PRP for the treatment of diabetic lower limb wounds
over a follow-up period of 12 weeks. During this
period, healing was observed in 13 of 19 wounds in the
treatment group compared to 9 of 21 in the control
group. The mean duration of healing was shorter in
Evidence on the use of platelet-rich plasma 115
the group using PRP (45 versus 85 days in the control
group). The authors reported that this was the first
randomized double-blind clinical trial conducted in
Russia. In addition, the authors concluded that PRP is
safe and efficient in the treatment of diabetic wounds.
Separate analysis of each study showed that two of
the four randomized controlled trials reported favor-
able outcomes with the topical use of PRP, a result that
was confirmed after combined analysis, i.e. using
either fixed or random effect meta-analysis models.
The present systematic review permits to under-
stand not only the problems encountered in the
construction and description of the studies published,
but also the need and importance of recognizing the
difficulties in the control of numerous intrinsic and
extrinsic variables involved in or related to chronic
wound healing, such as nutritional status, laboratory
tests, prevention and treatment protocols, and
professional qualification, among others. In addition,
factors such as quality of life of the patients and cost-
effectiveness of treatments might be indicated as
secondary outcomes in future studies.
Conclusion
The present systematic review and meta-analysis show
that there is a scientific evidence regarding favorable
outcomes of the use of PRP for the treatment of
diabetic ulcers. Despite the observation of positive
outcomes, especially in terms of healing rate, that
confirm the effectiveness of this approach, the use of
PRP for the treatment of diabetic ulcers cannot be
considered an isolated factor since a multiprofessional
treatment program for the patients was included in all
studies analyzed. These findings indicate PRP as a
treatment of choice for the topical care of chronic
wounds. Although the management and/or collection
of PRP is not as accessible as other treatments,
healthcare workers caring for chronic wounds will be
the key persons in this process, permitting any patient
to benefit from the use of PRP.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
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