O R I G I N A L A R T I C L E

Efcacy and safety of the use of autologous plasma rich in

platelets for tissue regeneration: a systematic review
M
a
Jos Martnez-Zapata, Arturo Mart-Carvajal, Ivan Sol, Ignasi Bolibar, Jos ngel Expsito,
Luciano Rodriguez, and Joan Garca
BACKGROUND: Autologous plasma rich in platelets
(PRP) is a derived blood product whose application in
clinical practice is growing. A systematic review was
conducted to evaluate its efficacy and safety.
STUDY DESIGN AND METHODS: A search was per-
formed in electronic databases. Randomized controlled
clinical trials (RCTs) in adult patients were included and
assessed for methodologic quality. The main outcomes
were tissue regeneration and safety. Relative risks
(RRs) and standardized mean differences (SMDs) were
calculated to show pooled estimates for these out-
comes. When the results heterogeneity was more than
50 percent, a sensitivity analysis was performed.
RESULTS: Twenty RCTs were included (11 of oral and
maxillofacial surgery, 7 of chronic skin ulcers, and 2 of
surgery wounds). Four RCTs evaluated the depth
reduction in gingival recession in chronic periodontitis;
the SMD was 0.54 (95% condence interval [CI], 0.16
to 0.92) mm, favorable to PRP. Three RCTs evaluated
the clinical attachment level in chronic periodontitis; the
SMD was 0.33 (95% CI, -0.71 to 1.37) mm. Six RCTs
assessed the complete skin epithelialization in wound
ulcers; the RR was 1.40 (95% CI, 0.85 to 2.31). Only 6
RCTs reported adverse effects without differences
between groups.
CONCLUSIONS: PRP improves the gingival recession
but not the clinical attachment level in chronic periodon-
titis. In the complete healing process of chronic skin
ulcers, the results are inconclusive. There are little data
about PRP safety. There are several methodologic limi-
tations and, consequently, future research should focus
on strong and well-designed RCTs that assess the effi-
cacy and safety of PRP.
A
utologous plasma rich in platelets (PRP) is a
product derived from fresh whole blood that
contains a high concentration of platelets
(PLTs) with healing anti-inammatory and pro-
regenerative properties that permit the body to heal tissue
wounds faster and more efciently. It is obtained from
the patients body through plasmapheresis technique.
Although fewinvestigators have quantied the concentra-
tion of PLTs obtained, it can be 338 percent more than the
normal total blood PLT count.
1
In recent years, the application of plasmapheresis has
been widely extended in diverse medical and surgical pro-
cedures,
2
especially in the elds of orthopedic surgery,
3
periodontic surgery,
4
maxillofacial surgery,
1
plastic
surgery,
5
thoracic surgery,
6
vascular surgery,
7-9
and
ophthalmology.
10
ABBREVIATIONS: GF(s) = growth factor(s); PRGF = plasma rich
in growth factors; PRP = plasma rich in platelets;
RCT(s) = randomized controlled trial(s); RR(s) = relative risk(s);
SMD(s) = standardized mean difference(s).
From the Iberoamerican Cochrane Center, Epidemiology and
Public Health Service, Hospital de la Santa Creu i Sant Pau,
Barcelona; CIBER Epidemiologia y Salud Pblica (CIBERESP);
Universidad Arturo Michelena and Iberoamerican Cochrane
Collaboration Network, Valencia (Venezuela); and the Universi-
tat Autnoma de Barcelona, Banc de Sang i Teixits de Catalu-
nya, Barcelona, Spain.
Address reprint requests to: M
a
Jos Martnez Zapata,
Iberoamerican Cochrane Center, Hospital de la Santa Creu i
Sant Pau, C/Sant Antoni Maria Claret 171, 08041 Barcelona,
Spain; e-mail: mmartinezz@santpau.cat.
This study was supported by the AETS, Instituto Carlos III,
Spain (Grant PI05/90173).
This study was presented in part at the 10th LatinCLEN
Congress, Barcelona, Spain, June 13-16, 2007.
Received for publication June 19, 2008; revision received
August 11, 2008; and accepted August 12, 2008.
doi: 10.1111/j.1537-2995.2008.01945.x
TRANSFUSION **;**:**-**.
Volume **, ** ** TRANSFUSION 1
Clinical evidence suggests that PRP could have ben-
ecial therapeutic effects on hard and soft tissue healing,
due to the contents of growth factors (GFs) stored in the
PLTs. When these GFs are released from the PLTs, they
trigger a tissue regeneration process.
7,8
Additionally, PRP
contains other intra- and extra-PLT components that
also contribute to regeneration. One example is bri-
nogen, which creates the brin network necessary
for cellular implantation and posterior cellular
multiplication.
11
Several commercially available methods to obtain
PRP concentrate are currently used in the clinical setting
and there are many types of kits, centrifuges, and vials
available. The usual methods consist of obtaining less
than 100 mL of fresh whole blood from the patient, and
separating and concentrating the PLTs by centrifugation.
Subsequently, before reinsertion into the patient, the PRP
is activated to produce PLT degranulation and clot
formation.
12
The substances used in activation are bovine
thrombin (which may cause immunologic problems and
Factor V deciencies)
13
or recombinant thrombin or
calcium, which have been proven to be safer proactive
options.
2
Despite several in vitro studies published, there are
very few clinical studies available on the efcacy of PRP.
Although the processing of autologous PRP is highly vari-
able, it is extensively used indifferent clinical settings. This
suggests that there is a need to synthesize current evi-
dence on the subject. Thus, we performed a systematic
review to evaluate the efcacy and safety of PRP in tissue
regeneration.
MATERIALS AND METHODS
Inclusion and exclusion criteria
We included all randomized controlled trials (RCTs) that
assess the efcacy and/or safety of PRP for healing and
regeneration of hard and soft tissues in any and all
medical and surgical procedures. Split-mouth-design
RCTs were included if they were randomized. In this
design each patient receives, simultaneously, the active
and control treatment in the right or in the left side of the
body (for example, of the mouth or the face).
14
Any RCT
crossover studies were also included when results regard-
ing the rst treatment period were reported.
We considered as relevant outcomes those referring
to any kind of tissue regeneration after PRP application
and/or safety related to PRP. Overall, the concept of
tissue regeneration referred to an improvement of the
functionality or complete tissue healing as specically
dened in the original studies. Different outcomes were
assessed, depending on the pathology (i.e., wound healing
in chronic skin ulcers, clinical attachment in chronic
periodontitis).
Literature search
We performed several computerized literature searches
for trials using the following search terms and combining
them: autologous plasma, autologous platelet, richgrowth
factor, plasma rich in growth factors (PRGF), wound,
tissue, bone, osseous, heal, and repair implant. This
search was ltered with the Cochrane methodologic lter
for clinical trials
15
in the following databases: The
Cochrane Central Register of Controlled Trials (CENTRAL;
The Cochrane Library 2006, issue 1), MEDLINE (accessed
via PubMed; 1966-2006), EMBASE (via OVID; 1974-2006),
and Science Citation Index (1945-2006). No language
restrictions were applied.
Reference lists of the most relevant studies and
engines search (http://www.google.com) were checked
for possible additional studies. Authors of the identied
studies were contacted in some cases.
16
Data extraction
Papers from the bibliographic search that met the inclu-
sion criteria were reviewed independently by two review-
ers and relevant data were extracted using a standardized
form.
Data was extracted regarding patient and interven-
tioncharacteristics, methodological quality and results for
each group of participants. The quality of the papers was
appraised using the Jadad scale.
17
This scale evaluates
whether trials are randomized or double blinded and
whether they include a description of dropouts, using a
score system. An additional point is given based on
whether the method of randomization and double-
blinding is appropriate or inappropriate. Based on the
resultant score, the studies were classied as high
quality (score of 4 or 5), moderate quality (score of 3), or
low quality (score < 3). A consensus between reviewers
was reached about the methodologic quality of each
study.
Statistical analysis
When possible, we pooled data from the included trials as
presented in the original publications in a meta-analysis
using a random-effects statistical model.
18
We calculated
risk ratios for binary outcomes and standardized mean
differences (SMDs) for continuous outcomes and their 95
percent condence intervals (95% CIs).
An analysis of heterogeneity was conducted by an I
2
test considering values of 25, 50, and 75 percent as a sign
of low, moderate, and high heterogeneity, respectively.
19
When I
2
values were 50 percent or greater, we conducted a
sensitivity analysis to explore the cause of heterogeneity.
We anticipated heterogeneity induced by quality of the
studies, disease severity, and the PRP processing method.
MARTNEZ-ZAPATA ET AL.
2 TRANSFUSION Volume **, ** **
When an acceptable homogeneity was observed,
(I
2
< 50%), the reviewers also estimated measures of clini-
cal effect suchas what patients neededtobe treated(NNT)
toobserve a clinical benet or the number of patients tobe
treated to detect an adverse event (NNH). The number
needed to treat is the estimated number of patients who
need to be treated with the new treatment rather than the
standard treatment for one additional patient to benet
(NNT) or to harm (NNH). All analyses were undertaken
using computer software (Review Manager [RevMan] 4.2,
The Nordic Cochrane Centre, Copenhagen).
RESULTS
Overall, 2016 citations were identied, of which 42 were
RCTs about PRP. Of these, 22 RCTs
10,16,20-39
were excluded
and 20 RCTs
1,4-7,40-55
fullled our eligibility criteria (Fig. 1).
The reasons of exclusion of RCTs are shown in Table 1.
Eleven studies
1,4,40-48
assessed the use of PRP in oral and
maxillofacial surgery (Table 2), 7
49-55
in cutaneous ulcers
(Table 3), and 2
5,6
in surgical wounds (Table 4).
PRP in oral and maxillofacial surgery
Of the 11 trials assessing the use of PRP in oral and max-
illofacial surgery, 5
40,42,44-46
had a parallel design, 1 study
1
did not specify the study design, and 5 studies
4,41,43,47,48
followed a split-mouth design. Although all studies were
randomized, none explained the process of allocation to
treatment as blinded to investigator (e.g., allocation by a
central ofce unaware of subjects characteristics or
sequentially numbered, sealed, opaque envelopes). In the
studies with split-mouth design
4,41,43,47,48
the treatment was
located in a specic side of the mouth based on a random
criterion. Three studies
4,41,46
were double blind and in
another 3
43,45,47
the evaluator was blinded to intervention.
The other 5 studies
1,40,42,44,48
were not blinded.
The numbers of patients included in each trial was
relatively small (n < 100) and no trial reported case sample
size calculation. Overall, the quality of ve studies
1,40,42,44,48
was low and moderate for the rest.
4,41,43,45-47
Five
RCTs
4,41,43,45,46
were conducted in patients with intrabony
periodontal defects secondary to chronic periodontitis,
three RCTs
42,47,48
were performed with patients that
needed sinus oor augmentations with or without
implants, two studies
40,44
were conducted in patients with
indicated dental extractions, and another study was con-
ducted in patients with maxillary bone grafts in mandibu-
lar defects secondary to extirpation of a benign or malign
tumor.
1
The outcomes of each clinical trial are specied in
Table 2. It was only possible to combine the results of 4 of
11 RCTs.
4,41,45,46
Excluding one RCT,
47
all of the non meta-analyzed
studies concluded that the PRP group showed better
results than the control group. Only two
1,41
of them speci-
ed the p value.
The results of four studies
4,43,45,46
were combined to
analyze the efcacy of PRP in depth reduction of gingival
recession (mm) versus a control group in patients suffer-
ing from chronic periodontitis. The mean effect showed a
greater reduction in patients in the experimental group
(153 patients; SMD, 0.54 mm; range, 0.16-0.92 mm;
Fig. 2).
Three studies
4,43,46
assessing the clinical attachment
level (mm) showed nonsignicant differences between
the experimental and control groups (126 patients; SMD,
0.33 mm; range, -0.71 to 1.37 mm; Fig. 2), and an impor-
tant heterogeneity was observed (I
2
= 86%). The heteroge-
neity was explained by differences in the criteria of disease
severity between studies. Results were homogeneous
(I
2
= 0%) when only studies
4,46
including patients at severe
stages were considered, and were favorable for the experi-
mental group (96 patients; SMD, 0.89 mm; range, 0.47-
1.31 mm).
Skin ulcers
Six
49-53,55
of the seven trials on this topic had a parallel
design and one
54
a crossover design. Two
50,55
of the seven
studies specied the process of random generation
sequence by computer numbers and three other studies
explained that treatment assignment was by sealed enve-
lopes
49,51
or by a centralized method independent of
the investigators.
55
The study by Driver and colleagues
55
explained the method of assignment blinding. Although
all studies (except Aguirre et al.
53
) were double-blinded,
only one
55
showed the blinding method. RCTs included a
relatively small number of patients (n < 100) and only two
trials
51,55
reported the sample size calculation. Conse-
quently, three studies
49,50,55
were of high quality, three
51,52,54
were of moderate quality, and one
53
was of low quality.
Four RCTs
49,50,53,54
included patients with chronic
ulcers of different etiology, two
51,52
with venous chronic
ulcers, and one with diabetic chronic ulcers.
55
It was only
possible to combine the results of the RCTs for the
outcomecomplete ulcer epithelialization. One RCT
53
did
not consider that outcome.
Results from six RCTs
49-52,54,55
assessing the efcacy of
autologous PRP or PLT factors obtained from autologous
PLTs were combined. A total of 122 patients were included
in the experimental group and 105 in the control group (
Fig. 3).
The results for the complete ulcer epithelialization
were not signicant between the experimental and
control groups (relative risk [RR], 1.40; range, 0.85-2.31).
However, heterogeneity was found among the studies
(I
2
= 56.8%) and consequently a sensitivity analysis was
performed. All RCTs had moderate quality except for
Knighton and colleagues,
49
Krupski and colleagues,
50
and
AUTOLOGOUS PRP FOR TISSUE REGENERATION
Volume **, ** ** TRANSFUSION 3
Driver and colleagues,
55
studies that had high quality.
When only those studies were analyzed, heterogeneity
increased to 62.1 percent and the results were signicant
and favorable to PRP (RR, 1.97; range, 1.19-3.25). Whenthe
studies
51,54
that obtained the PRP by applying a PLT lysate
were excluded, there was a decrease in the heterogeneity
between groups (from I
2
= 56.8% to I
2
= 44.9%) but the
results were similar to the principal analysis (RR, 1.65;
2016 studies identified by
CENTRAL, MEDLINE, EMBASE
and Science Citation Index databases
138 selected studies
1878 studies not relevant for the
review
42 clinical trials
99 studies relevant for the review
which did not meet inclusion criteria
20 included randomized controlled trials:
Odontology: 11
Skin ulcers: 7
Surgical wounds: 2
3 clinical trials identified by
www.google.es
22 excluded clinical trials:
Odontology: 2 noncontrolled clinical trials, 3 nonrandomized
controlled trials, 1 randomized controlled trial in which the
two treatment groups received PRP, 2 case series studies.
Ulcers: 5 nonrandomized controlled trials, 1
randomized controlled trial about homologous PRP; 1
case series study.
Traumatology: 3 nonrandomized controlled trials,
Surgical wounds: 1 nonrandomized controlled trial.
Other: 1 noncontrolled clinical trial on ophthalmology,
1 retrospective case series and 1 nonrandomized
controlled trial on neurosurgery.
Fig. 1. Trial ow.
MARTNEZ-ZAPATA ET AL.
4 TRANSFUSION Volume **, ** **
range, 0.73-3.70). When the analysis of the RCTs that
included ulcers of different etiologies was excluded, the
heterogeneity decreased to 10.6 percent and the results
were again similar to the principal analysis (RR, 1.23;
range, 0.90-1.41).
Surgery wounds
Two RCTs
5,6
assessed the use of PRP in surgery wounds.
The number of included patients was smaller (30 patients
or less) and none of the studies reported a priori sample
size calculation. Both studies were of low quality.
The study by Englert and coworkers
6
used a parallel
designandassessedtheautologous PRPgel comparedwith
a control group in patients who underwent bypass surgery
and had an external incision in the inferior extremity. The
experimental group showed better results in chest pain,
redness, and swelling. The pain was measured by an
ordinal scalethat scoredfrom0(nopain) to10(worst pain).
On Day 1, the score was 1.47 0.83 and 4.47 2, for the
experimental and control groups, respectively. Similarly,
the experimental group had favorable results in compari-
sonwiththecontrol groupintheoutcomeof low-extremity
pain (1.33 0.72 vs. 3.06 1.62, for the experimental and
control groups, respectively). However,
neither of the two outcome results
showed a signicance.
The study by Powell and colleagues
5
used a split-face design. Each patient
received both experimental and control
treatments in different sides of the face,
simultaneously. The autologous PRP gel
was compared in patients that under-
went face-lifts. This RCT included eight
patients. The experimental group
showed better results inthe outcomes of
ecchymosis and edema compared to the
control group, although results were not
signicantly different.
Safety of the treatments
Only 6 of 20 RCTs
4,42,47,50,52,55
reported the
treatment-related adverse events.
Overall, all studies agreed that there
were not treatment-related complica-
tions. Two RCTs included the type of
adverse event. Driver and coworkers
55
showed an increase in the blood urea
nitrogen in the control group, and an
increase in either the thrombin time or
the activated partial thromboplastin
time was observed in both treatment
groups (PRP and control). In the study
by Senet and colleagues,
52
two patients
reported dermatitis (one in each treatment group), one
patient developed an infection in an existing ulcer, and
one had thrombophlebitis (both in the PRP group).
DISCUSSION
The aim of this systematic review was to evaluate the ef-
cacy and safety of PRP for tissue regeneration. After an
exhaustive literature search, 20 RCTs that assessed the ef-
cacy of autologous PRP in oral and maxillofacial applica-
tions, chronic skin ulcer, and wound healing after surgery
were included.
In oral and maxillofacial surgery, four studies
4,43,45,46
with 153 patients suffering from chronic periodontitis
were meta-analyzed. The results of depth reduction of
gingival recession showed a signicant improvement in
the group treated with PRP. In the subgroup of patients
with more severe stage of the disease the outcome of
clinical attachment level showed better results than in
the subgroup of patients with an incipient illness. These
results suggest that patients with more severe chronic
periodontitis could benet from PRP.
In chronic skin ulcers, six studies
49-52,54,55
with 227
patients were included in the meta-analysis. Results
TABLE 1. Excluded studies and reasons of exclusion
Excluded studies (rst author, years) Causes of exclusion
Dentistry/oral and maxillofacial surgery
Camargo, 2005
20
Nonrandomized clinical trial
Franchini, 2005
21
Noncontrolled clinical trial
Froum, 2002
22
Three case series
Lekovic, 2002
23
RCTs; both arms receive PRP
Maiorana, 2003
24
Noncontrolled clinical trial
Monov, 2005
25
Nonrandomized clinical trial
Robiony, 2002
26
Five case series
Sammartino, 2005
27
Nonrandomized clinical trial
Skin ulcers
Atri, 1990
28
Nonrandomized sequential clinical trial (a
3-month treatment period rst and then
a 3-month period with experimental
treatment)
Margolis, 2001
29
Retrospective case series
Mazzuco, 2004
30
Nonrandomized clinical trial controlled with
a retrospective cohort of patients
Reutter, 1999
31
Nonrandomized clinical trial
Saldamalacchia, 2004
32
Nonrandomized clinical trial
Steed, 1992
33
Randomized clinical trial; PRP used is
homologous, not autologous
Tarpila, 1998
16
Nonrandomized clinical trial
Surgical wounds
Erlich, 2002
34
Nonrandomized clinical trial
Floryan, 2004
35
Nonrandomized clinical trial
Mishra, 2006
36
Nonrandomized clinical trial
Traumatology
Wright-Carpentier, 2004
37
Nonrandomized clinical trial
Ophthalmology
Korobelnik, 1996
10
Noncontrolled clinical trial
Neurosurgery
Castro, 2004
38
Nonrandomized clinical trial
Lowery, 1999
39
Retrospective case series
AUTOLOGOUS PRP FOR TISSUE REGENERATION
Volume **, ** ** TRANSFUSION 5
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MARTNEZ-ZAPATA ET AL.
8 TRANSFUSION Volume **, ** **
showed nonsignicant differences between experimental
and control groups in the complete epithelialization of
skin ulcers. The subgroup of RCTs that included chronic
ulcers of different etiologies added an important hetero-
geneity to the analysis. In the subgroup of studies with
diabetic ulcers there was a favorable but nonsignicant
tendency toward PRP. It is possible that ulcer etiology
inuenced the efcacy to PRP.
Regarding surgical wounds, two RCTs
5,6
with a total of
38 patients showed no differences between treatment
groups. The results may be explained by the smaller
sample size, quality of the studies, and the fact that the
selected outcomes, edema and ecchymosis, are difcult to
measure.
PRP safety has not been properly assessed across the
included studies. Only 6 of 20 RCTs reported the frequency
of adverse events and none showed a causal relation with
the PRP application.
It is certainly difcult to interpret the clinical rel-
evance of these systematic review ndings since the CIs
were large and study sample sizes were, in general, small.
Therefore, the statistical differences warrant caution
upon interpretation, as reported by other authors.
56
Well-designed, large RCTs with sample size calculations
exclusively based on clinically relevant differences are
needed.
Only three RCTs
49,50,55
in chronic skin ulcers were con-
sidered to be of high quality. However, primary and sec-
ondary outcomes were highly heterogeneous among
studies except for the principal outcomes in skin ulcers
(complete epithelialization or healing).
Despite these limitations, it was possible to combine
several RCTs that had a common endpoint in some of
the clinical areas assessed. PRP showed favorable
results compared to the control group in chronic
periodontitis.
Recently, a systematic review
57
has been published
about the effects of PLT-rich plasma on bone regeneration
in dentistry. Despite the fact that the search strategy of
studies was more limited than ours (pathology, language
restriction, and the EMBASE and Science Citation Index
databases were not used), there were some differential
methodologic questions, and the included studies were
not totally coincident, the conclusions were similar.
Currently, there are several ongoing trials (http://
www.clinicaltrials.gov/ct2/results?term=autologous+PLT)
assessing the efcacy of autologous PLT concentrate that
can add more evidence of the effects on the pathologies
included in our systematic review.
In conclusion PRP has been assessed thought RCTs in
several clinical areas. In our systematic review, treatment
of skin ulcers with PRP increased the percentage of total
recovery but not signicantly. In the treatment of chronic
periodontitis, there is animprovement inthe depth reduc-
tion of gingival recession and clinical attachment level at
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AUTOLOGOUS PRP FOR TISSUE REGENERATION
Volume **, ** ** TRANSFUSION 9
severe stages. In relation to the PRP for the treatment of
surgery wounds, there were not signicant differences
when compared with a control group. Due to the method-
ologic limitations of the RCT included in this systematic
review, there is a need for further RCTs to determine with
certainty the role of PRP for the tissue regeneration.
ACKNOWLEDGMENTS
We thank Eva Arnaiz and Mitsi Ito for the manuscript review and
editing.
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-10 -5 0 5 10
Favors control Favors PRP
Fig. 2. Efcacy of autologous PRP in chronic periodontitis.
PRP Control
RR (random)
Weight
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I C % 5 9 N / n N / n Study or sub-category % 95% CI
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Knighton 1990 17/21 2/13 10.58 5.26 [1.45, 19.15]
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Total events: 30 (PRP), 9 (Control)
Test for heterogeneity: Chi = 5.14, df = 2 (P = 0.08), I = 61.1%
Test for overall effect: Z = 1.10 (P = 0.27)
Total (95% CI) 122 105 100.00 1.40 [0.85, 2.31]
Total events: 77 (PRP), 53 (Control)
Test for heterogeneity: Chi = 11.57, df = 5 (P = 0.04), I = 56.8%
Test for overall effect: Z = 1.32 (P = 0.19)
0.01 0.1 1 10 100
Favors control Favors PRP
Fig. 3. Efcacy of autologous PRP in chronic skin ulcers.
MARTNEZ-ZAPATA ET AL.
10 TRANSFUSION Volume **, ** **
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