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Systematic Review
The Role of Platelet-Rich Plasma in Cartilage
Pathology: An Updated Systematic Review of the
Basic Science Evidence
Michael P. Fice, B.A., J. Chance Miller, B.A., Robert Christian, M.D.,
Charles P. Hannon, M.D., Niall Smyth, M.D., Christopher D. Murawski, B.S.,
Brian J. Cole, M.D., M.B.A., and John G. Kennedy, M.D., F.R.C.S.
Purpose: To review the basic science studies on platelet-rich plasma (PRP) for cartilage and determine whether there has
been an improvement in methodology and outcome reporting that would allow for a more meaningful analysis regarding
the mechanism of action and efficacy of PRP for cartilage pathology. Methods: The PubMed/MEDLINE and EMBASE
databases were screened in May 2017 with publication dates of January 2011 through May 2017 using the following key
words: “platelet-rich plasma OR PRP OR autologous conditioned plasma (ACP) OR ACP AND cartilage OR chondrocytes
OR chondrogenesis OR osteoarthritis OR arthritis.”Two authors independently performed the search, determined study
inclusion, and extracted data. Data extracted included cytology/description of PRP, study design, and results.
Results: Twenty-seven studies (11 in vitro, 13 in vivo, 3 in vitro and in vivo) met the inclusion criteria and were included
in the study. All of the studies (100%) reported the method by which PRP was prepared. Two studies reported basic
cytologic analysis of PRP, including platelet, white blood cell, and red blood cell counts (6.7%). Nine studies reported both
platelet count and white blood cell count (30.0%). Twelve studies reported platelet count alone (40.0%). Nine studies
(30.0%) made no mention at all as to the composition of the PRP used. PRP was shown to increase cell viability, cell
proliferation, cell migration, and differentiation. Several studies demonstrated increased proteoglycan and type II collagen
content. PRP decreased inflammation in 75.0% of the in vitro studies reporting data and resulted in improved histologic
quality of the cartilage tissue in 75.0% of the in vivo studies reporting data. Conclusions: Although the number of in-
vestigations on PRP for cartilage pathology has more than doubled since 2012, the quality of the literature remains limited
by poor methodology and outcome reporting. A majority of basic science studies suggest that PRP has beneficial effects on
cartilage pathology; however, the inability to compare across studies owing to a lack of standardization of study meth-
odology, including characterizing the contents of PRP, remains a significant limitation. Future basic science and clinical
studies must at a minimum report the contents of PRP to better understand the clinical role of PRP for cartilage pathology.
Clinical Relevance: Establishing proof of concept for PRP to treat cartilage pathology is important so that high-quality
clinical studies with appropriate indications can be performed.
See commentary on page 977
From the Section of Cartilage Restoration and Sports Medicine, Department
of Orthopaedics, Rush University Medical Center (M.P.F., C.P.H., B.J.C.), and
Department of Orthopaedic Surgery, Feinberg School of Medicine, North-
western University (R.C.), Chicago, Illinois; College of Physicians and Sur-
geons, Columbia University (J.C.M.), and Department of Orthopaedic
Surgery, Hospital for Special Surgery (J.G.K.), New York, New York;
Department of Orthopaedic Surgery, Miami University School of Medicine
(N.S.), Miami, Florida; School of Medicine, University of Pittsburgh (C.D.M.),
Pittsburgh, Pennsylvania, U.S.A.
The authors report the following potential conflicts of interest or sources of
funding: C.P.H. receives support from the Orthopaedic Research and Educa-
tion Foundation. B.J.C. receives support from Aesculap/B.Braun, Aqua Boom,
Arthrex, Athletico, Biomerix, Flexion, Geistlich, Giteliscope, JRF Ortho,
Medipost, National Institutes of Health (National Institute of Arthritis and
Musculoskeletal and Skin Diseases and the Eunice Kennedy Shriver Na-
tional Institute of Child Health and Human Development), Norvartis, Oper-
ative Techniques in Sports Medicine, Ossio, Regentis, Sanofi-Aventis,
Saunders/Mosby-Elsevier, Smith & Nephew, Tornier, and Zimmer. J.G.K.
receives support from Arteriocyte. Full ICMJE author disclosure forms are
available for this article online, as supplementary material.
Received February 6, 2018; accepted October 29, 2018.
Address correspondence to Charles P. Hannon, M.D., Rush University
Medical Center, Department of Orthopaedic Surgery, 1611 W Harrison St, Ste
200, Chicago, IL 60612, U.S.A. E-mail: charles.p.hannon@gmail.com
Ó2019 by the Arthroscopy Association of North America
0749-8063/18117/$36.00
https://doi.org/10.1016/j.arthro.2018.10.125
Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 35, No 3 (March), 2019: pp 961-976 961
Cartilage injuries and osteoarthritis are debilitating
conditions that represent significant treatment
challenges owing to the avascularity of chondrocytes
and their limited capacity for repair.
1-3
Injury to carti-
lage is common and can occur both in the normal aging
process and via traumatic injury. In the United States
the rate of knee articular cartilage surgery is increasing
at about 5% annually and is the most common
diagnosis for which arthroscopic procedures are per-
formed.
4
As a result, there is growing interest in
nonoperative treatments and biological adjuncts to
surgical treatments to promote cartilage healing and
curb degeneration.
Platelet-rich plasma (PRP) is an autologous blood prod-
uct that is centrifuged to isolate and concentrate platelets
to a level at least 3 to 5 times higher than endogenous
serum levels.
5
PRP contains a unique composition of
growth factors and cytokines, including vascular endo-
thelial growth factor (VEGF), fibroblast growth factor,
platelet-derived growth factor, insulin-like growth factor-
1, interleukin-1B, interleukin-10, and tumor necrosis
factor-B. These biological mediators are known to be
involved in healing through mechanisms such as angio-
genesis, collagen synthesis, and immune response regu-
lation.
1,5-7
Over the past decade, orthopaedic research and
treatments using PRP have become increasingly popular
owing to literature demonstrating its anti-inflammatory
and restorative function in musculoskeletal tissues such
as bone, tendon, ligament, and cartilage.
1,5,8-11
Owing to the relative ease of obtaining a serum
sample and the safety of its autologous origin, PRP has
gained significant interest as an adjunct to surgery and
as a nonoperative treatment.
12-15
PRP’s potential effects
in regulating the immune response, promoting angio-
genesis, and inducing cell differential make it an
intriguing option for the treatment of cartilage lesions.
However, the optimal clinical use of PRP for cartilage
pathology requires a better understanding of PRP’s
mechanism of action as both an adjunct to cartilage
repair as well as a nonoperative treatment modality for
osteoarthritis. A previous systematic review of the basic
science literature on PRP for cartilage pathology per-
formed by Smyth et al.
11
demonstrated the need for
standardization across study design so that meaningful
analysis and comparisons could be made. Literature
regarding PRP for cartilage pathology published prior to
2012 is heterogenous in methodology and outcome
reporting. The purpose of this study is to update a
previous systematic review by Smyth et al.
11
of basic
science studies on PRP for cartilage pathology by
reviewing the literature published since 2012. This
systematic review will determine whether there has
been an improvement in methodology and outcome
reporting that would allow for a more meaningful
analysis regarding the mechanism of action and efficacy
of PRP for cartilage pathology. The authors hypothe-
sized that recent literature on PRP for cartilage pathol-
ogy will be more consistent and comprehensive in
reporting methodology and outcome measures,
including the contents of PRP. It was also hypothesized
that this will allow a more detailed analysis of PRP’s role
in treating cartilage pathology that ultimately will
demonstrate several in vitro and in vivo benefits of PRP
for cartilage pathology.
Methods
Literature Search
This systematic review was conducted in accordance
with the guidelines set forth in the Cochrane Hand-
book.
16
Two authors (M.P.F., J.C.M.) independently
searched and selected eligible studies from the EMBASE
and PubMed/MEDLINE electronic database systems
with publication dates of January 2011 through May
2017. The search was performed in May 2017. A
starting date of January 2011 was chosen so that any
studies that may have been published during the time
frame of the previous search by Smyth et al.
11
but not
yet indexed on either EMBASE or PubMed would be
identified. The following key words were used in the
search: “cartilage OR chondrocyte OR chondrogenesis
OR osteoarthritis OR arthritis”AND “platelet-rich
plasma OR PRP OR autologous conditioned plasma OR
ACP”; these key words were identical to those of the
Smyth et al.
11
review. The reference list of all publica-
tions, including reviews identified in the search, were
screened for additional articles potentially not identified
through the EMBASE or PubMed/MEDLINE search.
Exclusion and Inclusion Criteria
Studies were included if they met the following criteria:
they (1) studied the effect of PRP in cartilage and chon-
drocytes and not in other tissue; (2) analyzed the use of
PRP, as defined by Smyth et al.,
11
for the treatment of
cartilage damage or injury and not in the context of
intervertebral disc disease or meniscal tears; (3) used PRP
that was not mixed with another reagent or material; (4)
were published in a peer-reviewed journal; (5) were
written in English; (6) used a control to compare PRP.
Articles that used PRP in the form of leukocyte platelet-
rich plasma (L-PRP), PRP gels, PRP releasate, and/or
activated PRP were included as long as they met the
previous inclusion criteria. All studies included in the
previous systematic review were excluded. Additionally,
all review articles, articles not written in English, and
clinical studies were excluded from the review.
962 M. P. FICE ET AL.
Two authors (M.P.F., J.C.M.) individually performed
the search, determined which studies met the exclusion
and inclusion criteria, and extracted data in accordance
with the PRISMA guidelines (Fig 1). Final results were
compared at the end of each stage to ensure accuracy
and compliance. For any articles that were not agreed
upon, a third author (C.P.H.) was consulted to make an
independent decision.
Data Extraction
A large-scale standardized data sheet was developed,
and 2 authors performed the data extraction. Data
collected included the description of PRP (platelet
concentration, white blood cell [WBC] concentration,
and red blood cell [RBC] concentration), growth factor
concentration, adhesive protein concentration, clotting
factor concentration, fibrinolytic factors, proteases and
antiproteases, basic proteins, membrane glycoproteins,
dense granule bioactive molecules, proinflammatory
cytokine concentration, anti-inflammatory cytokine
concentration, and other proteins.
In vitro studies were analyzed for cell viability, cell
proliferation, proteoglycan and type II collagen content,
gene expression, cell migration, cell differentiation, and
inflammatory mediation. In vivo studies were analyzed
for cell viability, gene expression, gross appearance of
cartilage repair, histologic assessment of cartilage repair,
proteoglycan content, collage type II deposition,
cartilage stiffness, and inflammatory mediation.
Results
A total of 775 articles were identified by the electronic
search; 49 duplicates were eliminated, and the
remaining 726 relevant articles were screened. After
abstract review, 652 articles were excluded because
they failed to meet the inclusion criteria. The remaining
74 articles were then analyzed for full-text review, and
an additional 47 articles did not meet inclusion criteria
(Fig 1). Thus, 27 articles met the inclusion criteria and
were included in the study.
3,13,17-41
Of the 27 articles,
11 were strictly in vitro studies
13,20,22,23,25,26,31,36,38-40
(Table 1), and 13 were strictly in vivo
Fig 1. Preferred Reporting
Items for Systematic
Reviews and Meta-Analyses
(PRISMA) diagram repre-
senting the process of indi-
vidual study inclusion after
application of the study al-
gorithm and each of the
exclusion criteria.
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 963
Table 1. In Vitro Studies on Platelet-Rich Plasma (PRP) for Cartilage Pathology Since 2011
Study PRP Cytologic Findings Study Design Outcomes Measured Results
Cavallo et al.
23
(2014)
Mean P-PRP platelet
concentration: 1.94
10
5
/mm
3
; mean L-PRP
platelet concentration:
9.29 10
5
/mm
3
; mean
P-PRP WBC
concentration: 5.5
10
3
/mm
3
; mean L-PRP
WBC concentration:
<200/mm
3
.
Chondrocytes were isolated from 4 human male
subjects and then seeded in 12-well plates at a
density of 0.25 10
5
cells/cm
2
and cultured for
7 days in P-PRP, L-PRP, or PPP at different
concentrations (5, 10, 20% vol/vol). Chondrocyte
growth was evaluated after 0, 3, and 7 days of
culture.
Cell proliferation, matrix
production, expression
of specific genes.
PRP contained several prochondrogenic
molecules such as TGF-B1 and FGF-B. All 3
formulations induced a dose-dependent
enhancement of chondrocyte growth. On day
7, P-PRP stimulated greater cell proliferation
compared with L-PRP and PPP. Higher levels
of hyaluronan were secreted by chondrocytes
grown in the presence of L-PRP compared
with other formulations, but effects of L-PRP
and P-PRP on secretion of lubricin were
similar.
Pereira et al.
18
(2013)
Mean platelet
concentration: 1 10
7
/
mL.
Chondrocytes were isolated from 4 men and 4 women
from femoral condyles, and isolated cells were
cultured in Coon’s modified Ham’s F12 with either
10% FCS or 5% PL. The number of cell doublings
was calculated for each passage.
Cell proliferation, ability to
maintain
redifferentiation
chondrogenic potential,
proinflammatory
potential of platelet
lysate.
Cells maintained in presence of PL had more
than 20 doublings compared with 4 for the
10% FCS condition. Chondrocytes cultured
in the presence of PL maintained a
chondrogenic potential and presented with
the typical chondrocyte appearance. PL
promotes proinflammatory cytokine
expression and secretion. Platelet lysate is a
source of growth factors able to induce a
selective chondrocyte recruitment.
Xie et al.
13
(2015)
Average platelet
concentration: 1.9-2.1
10
9
/mL; average
mononuclear cell
concentration: 11.8-
16.2 10
6
/mL.
PRP was prepared from 3 cows, and chondrocytes
were isolated from adult bovine knees. The day
before cyclic tensile strain, chondrocytes were
seeded onto 6-well plates. A pulsed waveform from
0%-16% elongation at 0.5 Hz frequency was
continuously applied for 48 hours, and after another
24 hours of incubation the chondrocytes and
supernatant medium were collected.
Concentration of platelets
and mononuclear cells in
PRP, effects of cyclic
tensile strain on
chondrocytes.
PRP increased type II collagen and aggrecan
messenger RNA expression. PRP mitigated
the increased matrix metalloproteinase-3
production and decreased tissue inhibitor of
metalloproteinase 1 secretion. PRP
ameliorated multiple cycle tensile strain-
mediated catabolic and inflammatory
responses in chondrocytes. Early PRP
application is more beneficial than late PRP
application.
Petrera et al.
20
(2013)
Average platelet
concentration: 1.22
10
6
/mL.
Chondrocytes were isolated from articular cartilage
harvested from 6- to 9-month old bovine
metacarpal-phalangeal joints. They were seeded on
calcium polyphosphate cylinders at a density of
160,000 cells/mm
2
and supplemented with fetal
bovine serum, PRP, or PPP at 5%. On day 5, the
concentration was increased to 20% and
supplemented with ascorbic acid. After 2 weeks of
culture, constructs were photographed and cartilage
heights determined.
Platelet count, mechanical
properties of PRP treated
cartilage, GAG content,
hydroxyproline content.
PRP in the culture media enhances the in vitro
formation of cartilage, with increased GAG
content and greater compressive mechanical
properties while maintaining characteristics
of hyaline phenotype.
(continued)
964 M. P. FICE ET AL.
Table 1. Continued
Study PRP Cytologic Findings Study Design Outcomes Measured Results
Hildner et al.
25
(2015)
Average thrombocyte
concentration: 1.0-2.0
10
9
/mL
Articular cartilage was from the femoral head of
patients undergoing total hip arthroplasty after
femoral neck fracture. Cells were expanded with 5%
PL or 10% FCS. ASCs from 8 donors and HACs from
3 donors were used to evaluate chondrogenic (re)
differentiation of ASCs and HACs. Micromass pellets
cultured for 5 weeks. Histologic evaluation was
performed on day 35.
Characterization of PL,
effect of PL on ASC and
HAC proliferation, GAG
quantification, qRT-PCR
gene analysis.
Both HACs and ASCs cultured with PL showed
strongly enhanced proliferation rates.
Redifferentiation of HACs was possible for
cells expanded up to 3.3 population
doublings. PL-expanded HACs demonstrated
better redifferentiation potential than FCS-
expanded cells. GAG quantification and qRT-
PCR of 10 cartilage related markers
demonstrated a tendency for increased
chondrogenic differentiation of PL-expanded
ASCs compared with cells expanded with
FCS. PL strongly induces proliferation of
ASCs, whereas the chondrogenic
differentiation potential is retained.
Kreuz et al.
26
(2015)
Average ACP platelet
concentration: 2- to 3-
fold increase. Average
PRP-A platelet
concentration: 0.6-1.3
10
10
/mL; average PRP-C
platelet concentration:
0.7-1.8 10
9
/mL;
average PRP-A WBC
concentration: <0.3
10
4
/mL.
Average PRP-C WBC
concentration: <0.5
10
4
/mL.
Human subchondral MPCs were isolated from
corticospongious bone of human femoral heads post
mortem. Chondrogenic differentiation of MPCs was
performed under serum-free conditions in high-
density pellet cultures. Migration of MPCs on
stimulation with PRP was analyzed in 96-multiwell
plates.
Determination of total
protein content of PRP
concentrates, tissue-
forming effects of PRP on
human subchondral
MPCs, PRP-mediated
chondrogenic
differentiation of human
subchondral MPCs,
measurement of
candidate chondrogenic
growth factor content in
PRP by ELISA.
MPCs cultured in the presence of 5% ACP, the
Regen ACR-C Kit, or the Dr. PRP Kit formed
fibrous tissue, whereas MPCs stimulated with
5% PRP-A or PRP-C developed compact and
dense cartilaginous tissue rich in type II
collagen and proteoglycans. All platelet
concentrations significantly stimulated
migration of MPCs. All platelet concentrates
except for Dr. PRP showed a proliferative
effect on MPCs.
Sakata et al.
31
(2015)
NA Cartilage tissue samples were obtained from the lateral
femoral condyle of 3-month-old bovine stifle joints.
Cells were seeded in a monolayer at 10
5
cells/well in
a 12-well culture plate in medium A with 1%ITS þ
Premix containing either 10% PRP or no PRP for
3 days. Media was harvested 3 days after PRP
treatment.
Cell proliferation, SZP
synthesis in knee joint
tissues, presence of SZP
in PRP, lubrication
properties of PRP.
PRP stimulated proliferation in cells derived
from articular cartilage, synovium, and
anterior cruciate ligament. PRP enhanced SZP
secretion from synovium and cartilage-
derived cells. Nonactivated and thrombin-
activated PRP decreased the friction
coefficient compared with saline and high
molecular weight hyaluronan. PRP contains
endogenous SZP.
Sundman et al.
22
(2014)
Mean platelet
concentration: 331
10
3
/
m
L231 10
3
;
mean WBC
concentration: 3.41
10
3
/mL 2.47 10
3
;
mean red blood cell
concentration: 3.8%
2.4%.
Human knee cartilage, subchondral bones, and joint
capsules (n ¼21) were from osteoarthritis patients
undergoing total knee arthroplasty. Three treatment
groups were established (HA, PRP [2.5 mL] and
untreated control). Total cellular RNA was extracted
from the synoviocytes. Before culture, 1 cartilage
explant from each sample was fixed and stained.
Histologic analysis of
cartilage, radiographic
scores of bone contour,
cytokine concentration
in media (IL-1B),
cartilage matrix gene
expression (aggrecan),
synoviocyte gene
expression.
Both PRP and HA treatments of osteoarthritic
joint tissues result in decreased catabolism,
but PRP treatment also resulted in a
significant reduction in MMP-13, an increase
in HAS-2 expression in synoviocytes, and an
increase in cartilage synthetic activity. PRP
acts to stimulate endogenous HA production
and decrease cartilage catabolism. PRP
showed similar effects as HA in the
suppression of inflammatory mediator
concentration and expression of their genes
in synoviocytes and cartilage.
(continued)
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 965
Table 1. Continued
Study PRP Cytologic Findings Study Design Outcomes Measured Results
Xie et al.
33
(2014)
NA Articular cartilage was removed from the knees and
hip joints of rabbits. Cell cultures used different
concentrations of PRP (0%, 5%, 10%, 20%, 30%).
Cells were washed and resuspended in PRP at 5
10
7
cells/mL. A constant compressive strain rate of
1 mm/min was applied, until a maximal force of
100 N was achieved to test the biomechanical
analysis.
Scanning electron
microscopy analysis of
chondrocyte-autologous
platelet-rich plasma gel
scaffolds, quantification
of growth factors in PRP,
effect of different
concentrations of PRP on
cell proliferation,
collagen and GAG
content analysis,
biomechanical analysis
of cartilage.
PRP may provide a suitable environment for the
proliferation and maturation of chondrocytes
and can be used as a promising bioactive
scaffold for cartilage regeneration. PRP
provides a high level of growth factors such as
TFG-B1 and FGF that can enhance cell
proliferation and/or matrix production.
Carmona et al.
40
(2016)
Mean platelet
concentration: P-PRP:
9.87 10
4
/
m
L; L-PRP:
3.128 10
5
/
m
L.
Mean WBC
concentration: P-PRP:
1.1 10
2
/
m
L; L-PRP:
3.51 10
4
/
m
L
30 cartilage explants were obtained from each horse; 6
experimental groups were set up (1 cartilage explant
healthy control without lipopolysaccharide,
` cartilage explant challenged with
lipopolysaccharide, 4 cartilage explant groups
cultured with L-PRG and P-PRG supernatants at 2
different concentrations [25% and 50%]). After
1 hour of incubation, L-PRG and P-PRG
supernatants were added to obtain concentrations.
All groups were cultured at 96 hours.
Histology via hematoxylin
and eosin staining,
chondrocyte apoptosis
gene expression via qRT-
PCR.
25% L-PRG has the most important anti-
inflammatory (MMP-13, ADAMTS-4, NF-kB)
and anabolic effect; 25% P-PRG supernatant
has important anabolic effects, but it induces
a high degree of chondrocyte apoptosis.
Durant et al.
39
(2016)
Mean platelet
concentration: 184.13
10
3
/
m
L; mean WBC
concentration: 0.75
10
3
/
m
L.
Peripheral blood from 8 human volunteers was
obtained and PRP was isolated. Human
chondrocytes were treated with PRP alone or PRP
plus corticosteroids or local anesthetics. Chondrocyte
viability was analyzed at 0, 5, 10, 30 minutes, and
proliferation was analyzed at 120 hours.
Luminescence and
radioactive thymidine
assays were used to
determine viability and
proliferation of
chondrocytes treated
with PRP.
PRP significantly limited the negative effect on
chondrocyte viability at tested time points for
those treated with anesthetics or
corticosteroids. PRP improves chondrocyte
proliferation.
Moussa et al.
38
(2017)
NA Chondrocytes were cocultured with different
concentrations of PRP (5%, 10%, 20%) that was
derived from 12 healthy human volunteers. Cells
were then analyzed for proliferation, autophagy,
apoptosis, and intracellular levels of different genes
via flow cytometry.
Proliferation, autophagy,
apoptosis, gene
expression via flow
cytometry, and ELISA.
PRP increases the proliferation of chondrocytes
and decreases apoptosis. PRP decreases
MMP3, MMP13, ADAMTS-5, IL-6, and COX-
2 in a dose-dependent manner. PRP increased
TGF-B, aggrecan, and COL2A1, IL-4, IL-10,
and IL-13.
Xu et al.
37
(2017)
Mean platelet
concentration: 2,000
10
9
/L; mean WBC
concentration: 0.15
10
9
/L.
Rabbit bone marrow stem cells were harvested from 6-
week old New Zealand white rabbits and L-PRP and
P-PRP was obtained. PRP scaffolds and transplanted
constructs were prepared as per Xie et al. Whole
blood analyses were performed to determine platelet
and leukocyte concentrations of whole blood and
PRP. Bone marrow stem cells were seeded onto cell
culture plates to determine the effects of PRP on the
NF-kB pathway.
Cell proliferation and
constituent components
of PRP was analyzed;
effects of PRP on NF-kB
were determined.
P-PRP has significantly lower concentrations of
leukocytes and proinflammatory cytokines
compared with L-PRP. P-PRP promotes
growth and chondrogenesis of rabbit bone
marrow stem cells.
(continued)
966 M. P. FICE ET AL.
studies
3,17,19,21,24,27-30,32,34,35,41
(Table 2). Three articles
included both in vitro and in vivo studies.
18,33,37
The
in vitro and in vivo components of each of these studies
were treated as separate studies for data analysis for a
total of 30 studies evaluated.
All of the studies (100%) reported the method by
which PRP was prepared; however, there were multiple
variations of the PRP preparation methods used. Two
studies reported basic cytologic analysis of PRP,
including platelet, WBC, and RBC counts (6.7%). Nine
studies reported both platelet count and WBC count
(30.0%). Twelve studies reported platelet count alone
(40.0%). Nine studies (30.0%) made no mention at all
as to the composition of the PRP used (Table 3).
In Vitro Studies
Of the 14 in vitro studies analyzed, 10 examined the
effect of PRP on chondrocytes (4 human,
18,23,38,39
3
bovine,
13,20,31
1 rabbit,
33
1 horse,
40
1 rat
36
), 1 exam-
ined the effect on human subchondral mesenchymal
progenitor cells,
26
1 examined the combined effect on
human adipose-derived stem cells and chondrocytes,
25
1 examined the effect on rabbit bone marrow stem
cells,
37
and 1 examined the combined effect on human
chondrocytes and synoviocytes
22
(Table 1).
Three (21.4%) of the studies
23,36,39
reported the in-
fluence of PRP on cell viability, with all 3 studies
demonstrating significant increases. Cell proliferation
was examined in 10 (71.4%) of the
studies,
18,23,25,26,31,33,36-39
and all of the studies showed
that PRP significantly increased proliferation of either
chondrocytes, mesenchymal progenitor cells, adipose-
derived stem cells, and/or synoviocytes.
The propensity for cell migration was reported in 2
(14.3%) studies,
18,26
and both demonstrated that PRP
increased cell migration activity. Likewise, the potential
for cell differentiation was reported in 3 (21.4%)
studies,
18,25,26
and in each of the studies there was a
significant increase in the differentiation capacity
(Table 4).
The effect of PRP on proteoglycan and type II collagen
content was less clear. Six of the 14 in vitro studies
reported data on proteoglycan and type II collagen
content (42.9%).
18,20,22,23,25,26
Three of the studies
revealed a significant increase in the synthetic capability
of chondrocytes,
20,25,26
2 of the studies demonstrated
no significant change,
18,22
and 1 reported a significant
decrease in type II collagen content.
23
Finally, gene expression and inflammatory mediation
were also analyzed. Three of the 9 studies reporting gene
expression, including COL1 and COL2, showed PRP to
have a significant increase,
18,23,25
whereas 6 additional
studies revealed that some genes significantly increased
and others significantly decreased.
13,22,36-38,40
Two of the
8studiesdescribinginflammatory mediation reported
Table 1. Continued
Study PRP Cytologic Findings Study Design Outcomes Measured Results
Yang et al.
36
(2016)
Mean platelet
concentration: 1-1.5
10
12
/L
Chondrocytes were isolated from cartilage tissue in the
knee joints of three 4-week-old male Sprague-
Dawley rat neonates. They were characterized by
immunohistochemical staining of collagen type II.
PRP was derived from the patient’s own blood. Five
different concentrations of PRP was studied (1%,
2%, 5%, 10%, 25% volume/volume). Total RNA
was isolated from the cells using TRIzol reagent
reverse transcription and was run according to the
manufacturer’s protocol.
Cell proliferation was
monitored using the
colorimetric water-
soluble tetrazolium salt
(CCK8) assay; total RNA
was used for qPCR of
specified genes, western
blotting for protein
expression, flow
cytometry.
10% PRP increased chondrocyte proliferation.
Il-1B induces cell apoptosis, but treatment
with PRP reduces overall apoptosis in IL-1B
treated chondrocytes. PRP significantly
reduces MMP production and promotes
anabolism of cartilage extracellular matrix
under IL-1B treatment.
ASC, adipose-derived stem cells; FCS, fetal calf serum; GAG, glycosaminoglycan; HA, hyaluronan; HAC, human articular chondrocytes; L-PRG, leukocyte- and platelet-rich gel; L-PRP,
leukocyte PRP; MPC, mesenchymal progenitor cell; NA, not applicable; PL, platelet lysate; PPP, platelet-poor plasma; P-PRG, pure platelet-rich gel; P-PRP, pure PRP; PRP-A, PRP by apheresis;
PRP-C, PRP by centrifugation; qRT-PCR, quantitative reverse-transcriptase-polymerase chain reaction; SZP, superficial zone protein; TGF-B1, transforming growth factor-B1; WBC, white
blood cell.
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 967
Table 2. In Vivo Studies on Platelet-Rich Plasma (PRP) for Cartilage Pathology Since 2011
Study
PRP Cytologic
Findings Study Design Outcomes Measured Results
Liu et al.
28
(2014)
Average platelet
concentration:
6.8-fold that of
whole blood.
Subchondral bone defect in 3
groups of rabbits (n ¼60
knees). PRP injections 1/
week for 3 weeks; 6 and
12 weeks after injection
rabbits were sacrificed and
distal femurs were dissected.
Platelet number,
concentrations of growth
factors of P-PRP and whole
blood, IL-1B concentration
in joint fluid, histologic
assessment (Mankin’s
scoring system).
Platelet concentration in P-PRP is 6.8-fold of
that in the whole blood. IL-1â level in the
P-PRP group was lower than in the HA
and control groups (P<.01). Restoration
of the defective cartilage as well as the
subchondral bone was better in the P-PRP
group than in the HA group or the control
group (P<.05). P-PRP is better than HA
in promoting the restoration of the
cartilage and alleviating the arthritis
caused by cartilage damage.
Pereira
et al.
18
(2013)
Average platelet
concentration:
110
7
/mL
Platelet lysates from 4 men
and 4 women were
prepared from femoral
condyles. Three-
dimensional micromass
pellets were maintained for
2-3 days in vitro before
subcutaneous implantation
in athymic mice. PL samples
were compared with those
grown with only 10% FCS.
Ectopic cartilage formation
was analyzed after 10 or 20
doublings in culture first.
Cell proliferation, histologic
assessment.
Cells maintained in presence of PL had more
than 20 doublings compared to 4 for the
10% FCS condition. PL promotes
proinflammatory cytokine expression and
secretion. Platelet lysate is a source of
growth factors able to induce a selective
chondrocyte recruitment.
Serra et al.
21
(2013)
NA Medial parapatellar
arthrotomy of the medial
femoral condyle in rabbits
(n ¼12). PRP-treated
animals received 7
injections of .25 mL PRP in
both knees, and placebo
group animals received 7
injections of .25 saline.
Animals sacrificed at 16 and
19 weeks.
Macroscopic analysis of
condylar surface,
microscopic study of defect
filling with normal matrix
staining and cell
morphology, biochemical
study of load and shearing
strengths.
Tissue treated with autologous PRP showed
a positive tendency over time, whereas
the placebo group was negative. At
19 weeks of age the PRP treatment did not
show better results than the placebo.
None of the treatments produced a repair
tissue that compared to the control model
(healthy cartilage).
Kutuk et al.
27
(2014)
Average platelet
concentration:
5.24-fold that of
whole blood.
Standard round burr defects
made in rabbit
temporomandibular joint.
Right joints received PRP
and left joints saline. After
4 weeks the rabbits were
sacrificed.
Histologic assessment via light
microscopy, scanning
electron microscopy analysis
of the ultrastructure of the
temporomandibular joint.
Although the regeneration of the
fibrocartilage and hyaline cartilage was
greater in the PRP group, no statistically
significant difference was found between
the 2 groups. Scanning electron
microscopy showed better ultrastructural
architecture of the collagen fibrils in the
PRP group.
Manafi
et al.
29
(2012)
Mean PRP platelet
count: 900,000/
mm
3
Skin and perichondrium was
removed from rabbit’s ear
and divided into 4 pieces (2
diced, 2 intact) and treated
with PRP or saline. Rabbits
were sacrificed at 12 weeks,
and cartilage was harvested.
Measurement of weight and
volume of implanted
cartilages, cartilage viability
via H&E staining.
In both the intact and diced cartilages adding
PRP resulted in increased regeneration of
chondrocytes. Adding PRP to intact
cartilages had a significant effect in
maintaining the graft’s weight and
volume.
Carneiro
et al.
30
(2013)
Platelet
concentration
range: 1.2-2.5
10
5
/
m
L
An osteochondral defect was
made in the trochlear
groove of sheep on both
knees. The left knee was left
alone, and the right knee
was filled with PRP gel. At
12 weeks sheep were
sacrificed and distal femurs
were analyzed.
Macroscopic analysis of
cartilage appearance,
microscopic analysis for
cartilage differentiation.
PRP has reparative properties of the joint
cartilage of sheep knees, but mostly by
stimulating the formation of
fibrocartilaginous tissue. Macroscopic
appearance was not uniform among
animals, nor was it different between the
right and left knees (PRP and control).
(continued)
968 M. P. FICE ET AL.
Table 2. Continued
Study
PRP Cytologic
Findings Study Design Outcomes Measured Results
Zhou et al.
34
(2016)
Mean platelet
concentration:
2.5 10
7
/mL
Osteoarthritis-like arthritis
was induced by intra-
articular injections of
monosodium iodoacetate
into both knee joints of rats.
Chondrocytes incubated
with or without platelets
were injected into the
articular cavity 2 weeks after
injury. Rats were sacrificed
at 4 or 8 weeks after
transplantation.
Chondrocyte gene expression,
chondrocyte protein
expression and
phosphorylation, histologic
and macroscopic evaluation
of cartilage repair.
Platelets significantly promote the
proliferation of chondrocytes while mildly
influencing anabolic and catabolic activity.
Chondrocytes cocultured with platelets
showed significantly increased production
of BMP7, which is responsible for
proliferation of chondrocytes.
Transplantation of platelet-treated
chondrocytes showed better cartilage
repair than the controls.
Milano
et al.
24
(2011)
NA A medial parapatellar
arthrotomy was made at the
medial femoral condyle of
sheep (n ¼30). Group 1
(n ¼15) had 5 intra-
articular injections of ACP
into the operated knee with
the first at 24 hours after
surgery and the rest every
week after for 4 times.
Group 2 (n ¼15) had
untreated operated knees.
Animals were sacrificed at 3,
6, and 12 months after
treatment.
Histologic analysis (tissue
morphology, chondrocyte
clustering, matrix staining)
of cartilage development
using H&E and Safranin-O
staining.
Histologic evaluation at 3 and 6 months
showed that ACP-treated animals had
significantly higher O’Driscoll scores than
control animals. At 12 months no
statistically significant difference was
observed between groups. Local injection
of ACP for treatment of full-thickness
cartilage injuries did not produce hyaline
cartilage, although it did promote the
reparative response of cartilage defect
until 6 months after treatment.
Bulam
et al.
19
(2015)
NA 6 cartilage grafts of rabbits (2
block circular grafts, 2
crushed cartilage grafts, 2
crushed cartilage grafts
wrapped with oxidized
regenerated cellulose) were
prepared and weighed.
Pockets were dissected
through 2 cm incisions on
the dorsum of rabbits.
0.5 mL autologous PRP for
experimental groups and
0.5 mL 0.9% NaCl for
control groups were injected
into the pockets where the
cartilage grafts were placed.
Grafts were removed
8 weeks later and then
weighed.
Weight loss/gain of cartilage
grafts, histopathologic
evaluation.
Although PRP-treated block cartilages lost
less percentage of weight, no significant
difference was found in histologic markers
of cartilage viability between PRP-treated
and non-treated cartilage grafts.
Danieli et al.
3
(2014)
Average platelet
concentration: >
10
6
/c
Lesions were made on rabbit
knees at the medial femoral
condyle. The left knee was
filled with PRP gel, and the
right knee was left
untreated. Animals were
euthanized 180 days after
surgery.
Histologic analysis of cell
morphology, surface
regularity, chondral
thickness and lateral
integration.
PRP significantly improved cell morphology,
surface regularity, chondral thickness, and
repair tissue integration compared with
control. Repair tissue was histologically
superior after 180 days when treated with
the platelet gel compared to untreated
group.
(continued)
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 969
Table 2. Continued
Study
PRP Cytologic
Findings Study Design Outcomes Measured Results
Boakye
et al.
17
(2015)
Mean platelet
concentration:
>1.1 10
6
/
m
L
Rabbit knees were randomly
treated with an injection of
0.5 mL of either PRP or
saline. Osteochondral grafts
were soaked in PRP or saline
for 10 minutes prior to
implantation. Rabbits were
sacrificed at 3, 6, or
12 weeks following surgery.
Histologic assessment of
articular cartilage via TGF-
B1 levels, histologic
assessment of synovium.
Articular cartilage of rabbits treated with
autologous osteochondral transplantation
and PRP exhibit increased TGF-B1
expression compared with those treated
with autologous osteochondral
transplantation and saline. There was a
higher percent concentration of
chondrocytes staining in the superficial
cartilage of PRP treated joints than
controls. Synovial tissue specimens
demonstrated hypertrophy in the PRP-
treated group when compared with the
saline-treated group microscopically.
Xie et al.
33
(2014)
NA Articular cartilage was
removed from the knee and
hip joints of rabbits and
enzymatically digested.
Different concentrations of
PRP (0%, 5%, 10%, 20%,
30%) were used.
Composites were
subcutaneously implanted
into BALB-c nude mice and
harvested at 6 weeks. A
constant compressive strain
rate of 1 mm/min was
applied, until a maximal
force of 100 N was achieved
to test the biomechanical
analysis.
Scanning electron microscopy
analysis of chondrocyte-
autologous platelet-rich
plasma gel scaffolds,
quantification of growth
factors in PRP, gross
evaluation of the in vivo
engineered composites,
histologic analysis of
cartilage formation, collagen
and GAG content analysis,
biomechanical analysis of
cartilage.
PRP may provide a suitable environment for
the proliferation and maturation of
chondrocytes and can be used as a
promising bioactive scaffold for cartilage
regeneration. PRP provides a high level of
growth factors such as TFG-B1 and FGF
that can enhance cell proliferation and/or
matrix production.
Smyth
et al.
32
(2013)
Mean platelet
concentration:
817.6 155.0
10
3
/
m
L; mean
white blood cell
concentration:
10.0 3.2
10
3
/
m
L; mean red
blood cell
concentration:
10.1 1.8
10
3
/
m
L.
An osteochondral lesion was
created at the lateral femoral
condyle of the left knee of
every rabbit. An
osteochondral lesion was
created in the right knee
and implanted with a graft
harvested from the left
knee. Grafts soaked in either
1 mL of PRP or saline
solution for 10 minutes
before placement into the
osteochondral lesion;
0.5 mL of PRP or saline
solution was additionally
administered as an intra-
articular injection. Rabbits
were sacrificed at 3, 6 or
12 weeks after initial
surgery.
Cytologic analysis of whole
blood and PRP aliquots,
macroscopic and histologic
appearance of the
osteochondral graft, GAG
content analysis.
When assessing graft integration, the mean
score for the PRP-treated group was
significantly higher than that for the
control group. PRP may improve the
integration of an osteochondral graft at
the cartilage interface and decrease graft
degeneration in an in vivo animal model.
There is increased GAG content in PRP-
treated samples, as well as greater type II
collagen immunoreaction compared with
the control group.
(continued)
970 M. P. FICE ET AL.
Table 2. Continued
Study
PRP Cytologic
Findings Study Design Outcomes Measured Results
Bahmanpour
et al.
41
(2016)
NA Full-thickness defect in the
trochlear groove was made
in 36 bilateral knees of 18
mature male rabbits. They
were randomly divided into
6 groups (I: control; II: PRP;
III: PRF; IV: gelatinþSDF1;
V: PRPþSDF1; VI:
PRFþSDF1). After 4 weeks
the specimens were
evaluated.
Macroscopic examination and
histologic grading,
immunofluorescent staining
for collagen type II, cartilage
marker genes by reverse
transcription-polymerase
chain reaction
Macroscopic evaluation revealed PRFþSDF1
was the highest, but PRP alone showed
significant improvement. Microscopic
analysis showed cartilage repair with PRP
alone was not significant.
Immunofluorescent staining for collagen
II demonstrated no change with PRP, but
significant distribution in the GelþSDF1,
PRPþSDF1, and PFRþSDF1 groups.
Reverse transcription-polymerase chain
reaction analysis revealed that mRNA
expression of SOX9 and aggrecan were
significantly greater in the PRFþSDF1,
PRPþSDF1, GelþSDF1, and PRF groups
but not the PRP group alone.
Xu et al.
37
(2017)
Mean platelet
concentration:
2,000 10
9
/L;
mean white blood
cell
concentration:
0.15 10
9
/L.
Rabbit bone marrow stem cells
were harvested from 6-
week old New Zealand
white rabbits and leukocyte
PRP and pure PRP were
obtained. PRP scaffolds and
transplanted constructs
were prepared as per Xie
et al. Whole blood analyses
were performed to
determine platelet and
leukocyte concentrations of
whole blood and PRP; 27
male mature New Zealand
white rabbits were used, and
a lateral para-patellar skin
incision was made. PRP
translates were introduced
into the incisions and
analyzed.
Macroscopic evaluation of
cartilage repair, micro-
computed tomography of
mineralized bone, histologic
analysis via H&E staining.
PRP provides better cartilage regeneration
based on histologic examination when
compared to leukocyte PRP.
Yokoyama
et al.
35
(2017)
NA Platelet-activated serum was
collected from 5 Japanese
white rabbits aged 12 weeks
using CellAID. PRP was
injected into the right knees
of Japanese white rabbits
(12 weeks) under
anesthesia. Knees were
injected with 1 mL of the
treatment (phosphate-
buffered saline, platelet
activated serum, Avastin,
platelet activated
serumþAvastin) solutions in
phosphate-buffered saline
weekly from weeks 1-7 and
weight distribution ratios
were measured. Rabbits
were killed at 12 weeks after
surgery by intravenous
overdose of anesthesia.
Medial and lateral tissues
from the femoral and tibial
ends of the right knees were
collected and fixed and
processed for histology and
staining.
Growth factor concentrations
were determined for VEGF,
PDGF-BB, and TGF-B;
histologic evaluation was
performed 12 weeks after
ACL transection; weight
distribution ratios of the
damaged limbs were
determined, and pain was
evaluated during weeks 1-7.
PRP showed therapeutic effects on cartilage
histologic repair and pain relief; Avastin
with PRP did not provide synergistic
effects.
ACP, autologous conditioned plasma; FCS, fetal calf serum; GAG, glycosaminoglycan; HA, hyaluronan; H&E, hematoxylin and eosin; PL,
platelet lysate; TGF-B1, transforming growth factor-B1.
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 971
PRP to have a significant increase,
18,23
and the remaining
6 studies demonstrated a significant decrease.
13,22,36-38,40
In Vivo Studies
The in vivo studies included used the following
animal models: 11 rabbit,
3,17,19,21,27-29,32,35,37,41
2
sheep,
24,30
2 mice,
18,33
and 1 rat.
34
PRP treatment was
studied in the context of focal cartilage lesions, and
most studies characterized factors such as histologic
appearance, biochemical matrix content, and/or load
and shearing strengths (Tables 1 and 5).
Of the 16 in vivo studies, only 1 study
33
reported data
on cell viability (6.3%), and the results showed no sig-
nificant change. Nine of the studies (56.3%) described
the effects that PRP had on the gross appearance of
cartilage repair. Five of those studies reported a signifi-
cant improvement in gross appearance
28,29,34,37,41
with
“restoration of the defected cartilage as well as the sub-
chondral bone.”
28
The other 4 studies stated that there
was no significant change in the gross appearance of the
cartilage with the use of PRP.
21,30,32,33
Proteoglycan content of cartilage repair with PRP
treatment was assessed histologically in 3 studies
(18.8%). Two of the studies showed a significant in-
crease in proteoglycan content,
32,34
whereas the third
study described no change.
33
Type II collagen deposi-
tion was also analyzed in 7 studies (43.8%). Four
studies reported no significant change in
deposition,
33,34,37,41
and 3 studies found significant in-
creases.
27,32,35
Kutuk et al.
27
specifically demonstrated
that there was improved organization of type II collagen
with PRP treatment in addition to the deposition.
All 16 studies (100%) reported a histologic assess-
ment of cartilage repair. Twelve of the studies reported
significant improvement in the quality of cartilage
repair tissue with PRP treatment,
3,17,18,24,27-30,32,34,35,37
and 4 studies demonstrated no change.
19,21,33,41
One
study that reported significant improvement in the
quality of cartilage tissue repair after PRP treatment
found that this was not maintained over time.
24
Two studies (12.5%) reported data on the strength
and stiffness of cartilage when treated with PRP. One
study reported no significant change,
33
whereas the
other study reported both decreased strength and no
significant change depending on the test adminis-
tered.
21
Finally, only 1 study (6.3%) reported data on
inflammatory mediation, and the data revealed a
significant decrease.
28
We also evaluated more than 100 additional param-
eters, including growth factors, adhesive proteins, pro-
and anti-inflammatory cytokines, and anabolic and
catabolic cytoskeletal molecules, in an attempt to
further identify factors of interest for future studies to
assess PRP efficacy. We were unable to find a single
parameter that was reported in >40% of studies
(Appendix 1).
Table 4. Variables Reported in Vitro
Outcome
Studies
Reporting, n (%)
Significant
Increase, n
No Significant
Change, n
Significant
Decrease, n
Cell viability 3 (21.4) 3 0 0
Cell proliferation 10 (71.4) 10 0 0
Proteoglycan and type
II collagen content
6 (42.9) 3 2 1
Gene expression 9 (64.3) 3 (6 studies had some
genes increase and
others decrease)
0 6 (6 studies had some
genes increase and
others decrease)
Cell migration 2 (14.3) 2 0 0
Cell differentiation 3 (21.4) 3 0 0
Inflammatory mediation 8 (57.1) 2 0 6
Table 3. Platelet-Rich Plasma Cytology Reporting in Basic Science Studies on Cartilage Repair Published Since 2011
Component
Reported
Studies, n (%)
Studies Not
Reporting, n (%)
Platelet count 21 (70.0) 9 (30.0)
WBC count 9 (30.0) 21 (70.0)
RBC count 2 (6.7) 28 (93.3)
Platelet þWBC þRBC count 2 (6.7) 28 (93.3)
Platelet þWBC count 9 (30.0) 21 (70.0)
Platelet count without WBCs or RBCs 12 (40.0) 18 (60.0)
No reference to Platelet, WBC or RBC count 9 (30.0) 21 (70.0)
RBC, red blood cell; WBC, white blood cell.
972 M. P. FICE ET AL.
Discussion
Although the number of basic science articles pub-
lished on PRP for cartilage pathology has more than
doubled since 2012, the quality of the literature
remains significantly limited by the lack of reporting of
recommended data. In the original systematic review
by Smyth et al.
11
that included 21 studies, only 1
(4.7%) reported a full cytology of PRP. In this updated
review of the original review by Smyth et al.,
11
27
articles were included, but only 2 (6.7%) studies
reported a full cytology of PRP. Moreover, 70.0% of
studies reported the platelet count, 6.7% of studies
reported the RBC count, and only 30.0% reported the
WBC counts within PRP. Furthermore, 30.0% of the
studies analyzed in this paper failed to document any of
the 3 parameters within their studies.
19,21,24,31,33,35,38,41
In all studies, the protocol of preparation and contents
of the PRP used should be clearly articulated and
reproducible so that results across studies can be
compared. Journals should consider establishing
guidelines that require all submitted studies on PRP to
report the method by which PRP was produced as well
as a detailed analysis of the biological contents.
When comparing studies on PRP in cartilage repair,
cell proliferation,
18,23,25,26,42-47
cell differentia-
tion,
18,25,26,44,45
and type II collagen and glycosami-
noglycan deposition
18,20,22,23,43,46-49
have consistently
been used to evaluate PRP efficacy in in vitro studies,
whereas histologic assessment
3,19,21,27,28,30,34,50-54
and
gross appearance
21,28,29,32-34,50,53,54
have been the
standard of evaluation of PRP in in vivo studies.
Although the contents of PRP reported in basic science
literature remains limited, a majority of the evidence
suggests that PRP has several effects on these param-
eters when treating cartilage pathology. All of
the in vitro studies (100%) that reported cell
proliferation demonstrated that PRP significantly
increases the proliferative capacity of treated
cells.
18,23,25,26,31,33,36-39
The2studies(1invivoand1
in vitro)
23,35
that reported on the effect of PRP on
VEGF expression found that VEGF levels were
increased, thus providing a potential mechanism for
induction of proliferation that was not identified in the
prior review by Smyth et al.
11
In addition, 3 of the 6
in vitro studies reporting data on proteoglycan and
type II collagen content demonstrated a significant
increase when treated with PRP,
20,25,26
with only 1
study showing a significant decrease.
23
Of the in vivo
studies, 12 of the 16 studies reporting on the histologic
assessment of cartilage demonstrated a significant in-
crease in the quality of cartilage
repair,
3,17,18,24,27-30,32,34,35,37
with the remaining 4
studies finding no change at all.
19,21,33,41
Some of the
aspects used to define quality of cartilage repair
included chondral thickness, tissue integration, cell
morphology, and surface regularity. Collectively, these
findings suggest that PRP has some benefittothe
overall growth and differentiation of the treated
chondrocytes in cartilage repair models, supporting its
use as an adjunct to bone marrow stimulation and
autologous osteochondral transplantation. However,
the extrapolation of these results to the efficacy of PRP
for treatment of osteoarthritis should be made with
caution. Only 2 basic science studies have specifically
looked at the use of PRP in an osteoarthritic
model.
22,34
In the setting of osteoarthritis, PRP has
been shown to have several anti-inflammatory effects,
which may result in improved clinical symptoms;
however, there is a lack of research on PRP’sefficacy
in preventing osteoarthritis disease progression.
In addition to its ability to increase chondrocyte pro-
liferation, PRP has been shown to induce chondrogenic
differentiation and matrix development. Petrera et al.
20
suggest that it is the ability of PRP to increase the overall
glycosaminoglycan content that promotes cartilage
repair. Although some studies demonstrated that this
repair maintains the hyaline phenotype characteristic
Table 5. Variables Reported in Vivo
Outcome
Studies
Reporting, n (%)
Significant
Increase, n
No Significant
Change, n
Significant
Decrease, n
Cell viability 1 (6.3) 0 1 0
Gene expression 4 (25.0) 3 (1 study had some genes
increase and others
decrease)
0 1 (1 study had some genes
increase and others
decrease)
Gross appearance of cartilage repair 9 (56.3) 5 4 0
Histologic assessment of cartilage repair 16 (100) 12 (1 study showed short
term growth increase,
but long term no
change)
40
Proteoglycan content 3 (18.8) 2 1 0
Type II collagen deposition 7 (43.8) 3 4 0
Cartilage stiffness 2 (12.5) 0 1 1 (showed both decreased
strength and no change)
Inflammatory mediation 1 (6.3) 0 0 1
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 973
and increases the overall compressive mechanical
properties of the tissue, other studies found that PRP
did not induce hyaline cartilage formation but was still
able to induce a reparative response.
24
Transforming
growth factor-B1 and fibroblast growth factor, both
found to be notably elevated in PRP, seem to facilitate
the overall matrix production and chondrocyte prolif-
eration by generating a scaffold that permits regenera-
tion and improved growth.
23,33
The ability of PRP to
stimulate endogenous hyaluronan production and
decrease cartilage catabolism may further promote
matrix synthesis.
22,31
The observed ability of PRP to inhibit catabolic pro-
cesses may also play a meaningful role in its efficacy
especially in osteoarthritis treatment. Matrix metal-
loproteinases (MMPs) are enzymes with the potential
to degrade multiple extracellular matrix proteins and
may inhibit the development of matrix formation
during the healing process. The ability of PRP to
significantly reduce MMP-3 and MMP-13 activity when
administered shortly after injury improves matrix for-
mation and the healing process.
13,22
However, this
process seems to be time dependent since delayed
administration of PRP after injury shows less effect and
may, in fact, increase MMP-13 activity.
13
This suggests
that PRP’s effects are multifactorial and that the time of
administration may change the overall efficacy and
anti-inflammatory potential, which is important when
considering its clinical implications. However, the effect
of PRP on the inflammatory milieu is not clearly un-
derstood. Some studies have argued that PRP’s ability to
induce transitory proinflammatory cytokines promotes
cell migration postinjury via chemoattractant effects
that seem to be chondrocyte specific.
18
Conversely,
other studies have shown that PRP inhibits inflamma-
tory cytokines and have concluded that this leads to a
decrease in secondary matrix damage mediated by the
proinflammatory process.
13,22
Limitations
The greatest limitation of this study that prevents
detailed analysis and comparison across studies is the
lack of consistent methodology and outcome reporting
as previously discussed. In addition, the study is limited
by the databases chosen to search, which may lead to
selection bias. There are also several limitations
inherent to in vivo and in vitro studies. For in vivo
studies, cartilage lesions are distinctly different in
animals than humans. The lesions in animals are typi-
cally smaller, and the thickness of cartilage is also
thinner. This study is also limited by a lack of evaluation
of the risk of bias of included studies. Unfortunately,
there are no validated tools to evaluate the presence of
bias in basic science research. A validated tool to inde-
pendently assess the quality and risk of bias in these
studies would provide a more objective evaluation for
future systematic reviews of the topic. Owing to these
limitations, it is difficult to extrapolate results to a
clinical setting; however, basic science research is still
critical to evaluate for proof of concept for PRP for
cartilage therapy.
Conclusions
Although the number of investigations on PRP for
cartilage pathology has more than doubled since 2012,
the quality of the literature remains limited by poor
methodology and outcome reporting. A majority of
basic science studies suggest that PRP has beneficial
effects on cartilage pathology; however, the inability to
compare across studies owing to a lack of standardiza-
tion of study methodology, including characterizing the
contents of PRP, remains a significant limitation. Future
basic science and clinical studies must at a minimum
report the contents of PRP to better understand the
clinical role of PRP for cartilage pathology.
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Appendix 1. Variables Reported in Basic Science Studies on Platelet-Rich Plasma for Cartilage Pathology Published Since 2011
No. of Studies Reporting Increase, Decrease, or No Change?
Growth factor concentrations
Epidermal growth factor (EGF) 2 (1 in vivo; 1 in vitro) Increase
Platelet-derived growth factor A+B (PDGF AþB) 9 (4; 5) Increase
Transforming growth factor-B1 (TGF-B1) 12 (5; 7) Increase (1 in vivo study found no change)
Insulin-like growth factor- I, II (IGF- I, II) 3 (1; 2) Increase
Vascular endothelial growth factor (VEGF),
endothelial cell growth factor (ECGF)
2 (1; 1) Increase
Basic fibroblast growth factor (bFGF) 2 (1; 1) Increase (in vivo); no change (in vitro)
Fibroblast growth factor-2 (FGF-2) 2 (0; 2) Increase
Fibroblast growth factor-18 (FGF-18) 0 NA
Bone morphogenetic protein-2 (BMP-2) 1 (0; 1) No change
Bone morphogenetic protein-7 (BMP-7) 1 (1; 0) Increase
Hepatocyte growth factor (HGF) 1 (0; 1) Increase
Adhesive protein concentration
Fibrinogen 0 NA
Fibronectin 0 NA
Vitronectin 0 NA
Thrombospondin-1 1 (0; 1) Decrease
Clotting factor concentration
Factor V 0 NA
Factor XI 0 NA
Protein S 0 NA
Antithrombin 0 NA
Fibrinolytic factors
Plasminogen 0 NA
Plasminogen activator inhibitor 0 NA
Alpha-2 antiplasmin 0 NA
Proteases and antiproteases
Tissue inhibitor of metalloproteinases (TIMP-4) 1 (0; 1) Increase
Metalloprotease-4 0 NA
Alpha1-antitrypsin 0 NA
Basic proteins
Platelet factor 4 0 NA
B-thromboglobulin 0 NA
Endostatins 0 NA
Membrane glycoproteins
Cluster of differentiation CD40 ligand (CD40L) 0 NA
P-selectin 0 NA
Dense granule bioactive molecules
Serotonin 0 NA
Histamine 0 NA
Dopamine 0 NA
Adenosine diphosphate (ADP) 0 NA
Adenosine triphosphate (ATP) 0 NA
Ca2þ0NA
Catecholamines 0 NA
Proinflammatory cytokine concentration
Interleukin-1 alpha (IL-1a) 0 NA
Interleukin-1 beta (IL-1b) 5 (2; 3) Increase (1: in vitro); decrease (4: 2 in vivo and 2
in vitro)
Interleukin-2 (IL-2) 0 NA
Interleukin-6 (IL-6) 4 (0; 4) Increase (2); no change (1); decrease (1)
Interleukin-7 (IL-7) 0 NA
Interleukin-8 (IL-8) (CXCL8) 2 (0; 2) No change
Tumor necrosis factor-alpha (TNF-a) 4 (1; 3) No change (2 in vitro); decrease (2: 1 in vivo and 1
in vitro)
Interferon-alpha (IFN-a) 0 NA
Interleukin-12 (IL-12) 0 NA
Interleukin-15 (IL-15) 0 NA
Interleukin-17 (IL-17) 0 NA
Interleukin-18 (IL-18) 0 NA
(continued)
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 976.e1
Appendix 1. Continued
No. of Studies Reporting Increase, Decrease, or No Change?
Natural killer B-cell cytokines (NK-B cytokines) 3 (1; 2) No change (2: 1 in vivo and 1 in vitro); decrease
(1 in vitro)
Anti-inflammatory cytokine concentration
Interleukin-1 receptor antagonist (IL-1RA) 0 NA
Interleukin-4 (IL-4) 1 (0; 1) Increase
Interleukin-5 (IL-5) 0 NA
Interleukin-10 (IL-10) 2 (0; 2) Increase
Interleukin-13 (IL-13) 1 (0; 1) Increase
Interferon-gamma (IFN-g) 0 NA
Other proteins
Activin A 0 NA
Advanced glycosylation end product (AGE) 0 NA
Agrin 0 NA
Brain-derived neurotrophic factor (BDNF) 0 NA
Chemokine (C-C motif) ligand 2 (CCL2) 0 NA
Chemokine (C-C motif) ligand 5 (CCL5) 0 NA
Chemokine (C-C motif) ligand 20 (CCL20) 0 NA
Chemokine (C-X-C motif) ligand 1 (CXCL1) 0 NA
Chemokine (C-X-C motif) ligand 2 (CXCL2) 0 NA
Chemokine (C-X-C motif) ligand 3 (CXCL3) 0 NA
Chemokine (C-X-C motif) ligand 5 (CXCL5) 0 NA
Chemokine (C-X-C motif) ligand 7 (CXCL7) 0 NA
Chemokine (C-X-C motif) ligand 10 (CXCL10) 0 NA
Ciliary neurotrophic factor (CNTF) 0 NA
Cluster of differentiation 86 (CD86) 0 NA
Colony-stimulating factor 2 (CSF2) 0 NA
Fas ligand 0 NA
Fractalkine 0 NA
Intercellular adhesion molecule 1 (ICAM1) 0 NA
Interleukin 1 receptor-like 2 (IL1RL2) 0 NA
L-selectin 0 NA
Leptin 0 NA
Matrix metalloproteinase 1 (MMP1) 2 (0; 2) No change (1); decrease (1)
Matrix metalloproteinase 2 (MMP2) 0 NA
Matrix metalloproteinase 3 (MMP3) 3 (0; 3) No change (2); decrease (1)
Matrix metalloproteinase 8 (MMP8) 0 NA
Matrix metalloproteinase 9 (MMP9) 1 (0; 1) No change
Matrix metalloproteinase 13 (MMP13) 7 (1; 6) Increase (1); no change (1); decrease (4: 1 in vivo
and 4 in vitro)
Prolactin receptor 0 NA
Tissue inhibitor of metalloproteinases 1 (TIMP1) 3 (0; 3) Increase
Regulated on activation, normal T cell expressed
and secreted (RANTES)
0NA
Monocyte chemoattractant protein-1 (MCP-1) 0 NA
Macrophage inflammatory protein-1a (MIP-1a) 0 NA
Granulocyte-colony stimulating factor (G-CSF) 0 NA
Granulocyte-macrophage colony stimulating
factor (GM-CSF)
0NA
Eotaxin 0 NA
Macrophage inflammatory protein-1b (MIP-1b) 0 NA
Cartilage oligomeric matrix protein (COMP) 2 (0; 2) No change (1); decrease (1)
Collagen type 1 (COL1A1) 6 (2; 4) No change (3: 1 in vivo and 2 in vitro); decrease
(3: 1 in vivo and 2 in vitro)
Collagen type 2 (COL2A1) 12 (6; 6) Increase (6: 3 in vivo and 3 in vitro); no change
(6: 3 in vivo and 3 in vitro)
Collagen type 3 (COL3A1) 0 NA
(continued)
976.e2 M. P. FICE ET AL.
Appendix 1. Continued
No. of Studies Reporting Increase, Decrease, or No Change?
A disintegrin and metalloproteinase with
thrombospondin motifs-5 (ADAMTS-5)
3 (1; 2) Decrease
Aggrecan 9 (3; 6) Increase (5: 2 in vivo and 3 in vitro); no change
(2: 1 in vivo and 1 in vitro); decrease (2 in vitro)
Protein 10 (IP-10) 0 NA
NA, not applicable.
EVIDENCE ON PRP FOR CARTILAGE PATHOLOGY 976.e3
