Contents lists available at ScienceDirectJournal of Orthop.docx

Contents lists available at ScienceDirect
Journal of Orthopaedics
journal homepage: www.elsevier.com/locate/jor
Review Article
Treating hand and foot osteoarthritis using a patient's own
blood: A
systematic review and meta-analysis of platelet-rich plasma
Adam Evansa,∗ , Maryo Ibrahima, Rand Popeb, James Mwangia,
Mina Botrosa,
Shepard P. Johnsonc, Salam Al Kassisc
a Meharry Medical College, 1005 Dr DB Todd Jr Blvd,
Nashville, TN, 37208, USA
b Vanderbilt University School of Medicine, 1161 21st Ave
South, Nashville, TN, 37232, USA
c Vanderbilt University Medical Center Department of Plastic
Surgery, D-4207 Medical Center North, 1211 Medical Center
Drive, Nashville, TN, 37212, USA
A R T I C L E I N F O
Keywords:
Platelet-rich plasma
Osteoarthritis
Cartilage
Intra-articular injections
Hand

Foot
Ankle
A B S T R A C T
Background: This study summarizes all literature investigating
platelet-rich plasma (PRP) in the treatment of
osteoarthritis of the hands and feet.
Materials & methods: This is a PRISMA compliant systematic
review of 7 databases and includes a meta-analysis
of randomized controlled trial (RCT) data on pain and function.
Results: Nine articles were included in the review. Meta-
analysis of 4 RCTs shows PRP significantly improves
pain and function versus control. More results are significant at
longer duration follow-up.
Conclusions: PRP improves pain and function of osteoarthritis.
Heterogeneity and risk-of-bias limit current data,
requiring more RCTs to determine any regenerative potential of
PRP.
Prospero Systematic Review Registration Number: 136582.
1. Introduction
Osteoarthritis is the most common form of degenerative joint
dis-
ease and the leading cause of disability in elderly populations.
In 2012,
approximately 52.5 million (22.7%) adults in the United States
carried
a diagnosis of osteoarthritis. As the elderly population grows,
this in-
cidence is expected to increase.1–3 In addition to the health
implica-
tions, osteoarthritis is the second most costly condition in the
nation,
with medical expenditures reaching an excess of $16.5 billion

yearly.1–4
Healthcare costs and high incidence make this degenerative
condition
one of the most important chronic conditions in the world.
Osteoarthritis is the breakdown of joint cartilage and its
underlying
bone resulting in pain, stiffness, and a loss of joint function.
Some joints
experience osteoarthritis as a normal process of aging,5 while
other
joints such as the ankle predominately experience osteoarthritis
sec-
ondary to trauma that exposes subchondral bone.6 The size of
the os-
teochondral lesion not only correlates to pain, but predisposes
to os-
teoarthritis.7
On a molecular level, hyaline cartilage erosion and an
imbalance of
pro- and anti-inflammatory cytokines, such as interleukin-1β
(IL-1β)
and matrix metalloproteinases (MMPs), cause synovitis.
Repetitive
mechanical stress results in the remodeling of subarticular bone,
osteophyte formation, and capsular swelling which leads to the
clinical
sequelae of osteoarthritis with both the incidence and severity
being
affected by risk factors including genetics, traumatic injury, and
obe-
sity.8–12 As the disease progresses, the erosion of hyaline
cartilage

within the joint heals poorly due to minimal intrinsic circulation
and
ability for regrowth or regeneration.
There are no curative medications, however, in 2019 an exciting
discovery was made that the potential for regrowth or
regeneration of
cartilage is the greatest in the most distal cartilage, such as of
the hands
and feet.13 Currently, physicians and patients pursue
symptomatic
management including thermal modalities, topical capsaicin,
non-ster-
oidal anti-inflammatory drugs, and steroid injections.14
Arthroplasty
(e.g. hip replacement) is profoundly effective for large joint
osteoar-
thritis,15–17 but surgical interventions for small joint hand and
foot
osteoarthritis remain meager and come at the expense of
functionality
(e.g. joint fusion, denervation).18,19 Therefore, interest of
patients and
providers in intra-articular injection of autologous growth
factors,
platelet-rich plasma (PRP) in particular, is an exciting option
that treats
pain, and also carries a possibility for enhancing chondrocyte
activity
that is the most pronounced in the small joints of the hand and
foot.20–22 While PRP treatments have been reviewed in the
context of
knee and large joint osteoarthritis,21–23 no such review has
been
https://doi.org/10.1016/j.jor.2020.01.037

Received 22 January 2020; Accepted 25 January 2020
∗ Corresponding author. Washington University School of
Medicine, Department of Surgery, Division of Plastic and
Reconstructive Surgery, 660 S. Euclid Ave, St.
Louis, MO, 63110, USA.
E-mail address: [email protected] (A. Evans).
Journal of Orthopaedics 18 (2020) 226–236
Available online 28 January 2020
0972-978X/ © 2020 Professor P K Surendran Memorial
Education Foundation. Published by Elsevier B.V. All rights
reserved.
performed on small, distal joint osteoarthritis.
1.1. PRP preparation and mechanism
PRP is an autologous product of whole blood centrifugation
which
separates blood by density into cellular layers and a supernatant
layer.
The supernatant is further divided, often by pipetting or by a
second
centrifugation step, into a platelet-rich segment called platelet-
rich
plasma (PRP) and a platelet-poor segment termed platelet-poor
plasma
(PPP). PRP contains a platelet concentration 2–5 times higher
than that
of normal blood. Many protocols for preparing PRP exist. One
re-

searched variant is whether to include the leukocyte-containing
buffy
coat; the inclusion of this layer provides the designation
leukocyte-rich
(LR) PRP while the absence of leukocytes is termed leukocyte-
poor (LP)
PRP.24 LP-PRP is the standard preparation for osteoarthritis
due to in-
vitro and animal studies demonstrating that LR PRP induces
more IL-1β
and less chondrocyte proliferation than LP PRP.25–28
Furthermore, In-
travia et al. tested LR versus LP PRP and both significantly
inhibited
bacterial growth when compared to normal blood culture, and
had no
significant difference between each other.29
The biomolecular mechanisms by which PRP functions is a
topic
heavily under study. The current understanding is that local
stimuli
induce platelet release of a subset of their cytokine and growth
factor
containing α-granules. In the instance of osteoarthritis, these
molecules
act predominately via anti-inflammatory cascades to reduce the
pain of
osteoarthritis.23,30 The anti-inflammatory effect of PRP
includes sup-
pressing the actions of the inflammatory and catabolic cytokines
tumor
necrosis factor α (TNF-α) and interferon-γ in endothelial
cells.31 Sur-
prisingly, PRP also induces molecules associated with sterile in-
flammation, such as interleukin-1β (IL-1β), for which the net

effect on
osteoarthritis chondrocytes is a production of molecules that
would
ordinarily not be produced in the presence of IL-1β, such as the
re-
generative building blocks type II collagen and aggrecan, while
still
resulting in increased production of the chondroprotective
hyaluronan
by synoviocyte in response to IL-1β.32–34 Another growth
factor,
transforming growth factor β1 (TGF-β1), has an antagonistic
effect to
IL-1β while also increasing differentiation of mesenchymal
stem cells
into chondrocytes.35,36 PRP is thought to protect cartilage
largely due
to IGF-1 and TGF-β1, which promote cell survival and
deposition of
extracellular matrix.37 Vascular endothelial growth factor
(VEGF) is an
important influencer of angiogenesis that is found in PRP,
however, its
antagonist, thrombospondin (TSP1), is interestingly found in the
highest physiologic concentration in platelet α-granules. The net
effect
of these pro- and anti-angiogenesis proteins may correct the
pathologic
angiogenesis found in osteoarthritis.37–40
These findings promote that PRP may mediate cartilage
regenera-
tion in addition to reducing pain. Therefore, this systematic
review and
meta-analysis aims to summarize all literature on PRP applied
for the

treatment of small, distal joint osteoarthritis of the hands and
feet in
order to investigate the therapeutic efficacy and regenerative
potential
of PRP.
2. Methods
This study was done in accordance with the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines
with the protocol ID 136582 being established prior to the
conduct of
the review.41
2.1. Search strategy
Independent literature searches were performed by two authors
(M.I. and J.M.) of all published articles up to June 2019
utilizing:
Cochrane Library, Ovid Medline, Ovid Embase, Web of
Science,
clinicaltrials.gov, World Health Organization Clinical Trials
Registry,
and EBSCO. The search was conducted in June of 2019 using
the search
terms: “platelet-rich plasma” OR “platelet rich fibrin” OR
“platelet-rich
fibrin” OR “platelet gel” OR “autologous conditioned plasma”
OR “pure
platelet-rich-plasma” OR “platelets” OR platelet concentrate”
OR “prp”
OR “prgf” OR “acp” AND “arthritis” OR “osteoarthritis” OR
“OA.” The
search strategy was designed and altered as necessary and

appropriate
to the different databases (Appendix). Bibliographies of
included stu-
dies were also searched. An additional reviewer (A.E.) assisted
in the
discussion of study selection in any instance of disagreement
between
the two reviewers. To capture all published clinical trials, both
rando-
mized controlled trials (RCTs) and non-randomized studies of
inter-
ventions (NRSI) were included. The largest cohort was included
in the
study if multiple publications described the same cohort. Data
extrac-
tion was performed by one reviewer (M.I.) using a piloted form
excel
spreadsheet method, with a second reviewer (A.E.) checking
over 90%
of the extracted data. Experts in the field of plastic &
reconstructive
surgery and in the application of PRP were consulted and
included in
the study.
2.2. Inclusion and exclusion criteria
Included studies: 1) treated patients over the age of 18, 2) used
intra-articular injections of PRP, 3) treated osteoarthritis and
os-
teochondral lesions affecting a joint of the hand and foot, 4) had
a
minimum follow-up of at least 3 months, 5) were published in
English.
Excluded studies: 1) were duplicates of studies or cohorts, 2)

treated
conditions different than osteoarthritis or osteochondral lesions,
e.g.
(rheumatoid arthritis, epicondylitis, carpal tunnel, plantar
fasciitis), 3)
treated joints other than the hand, wrist, foot, or ankle, e.g.
(knee os-
teoarthritis, hip osteoarthritis), 4) pending trials, 5) studies with
absent
baseline functional/pain data, 6) animal studies, case reports,
review
articles, or retrospective studies, 7) non peer-reviewed “grey”
literature.
2.3. Risk of bias
Risk of Bias assessment was performed at a study and outcome
level
through use of the Cochrane risk-of-bias tool for randomized
controlled
trials. Study sources of funding and reported conflicts of
interest were
recorded.
2.4. Outcomes
The primary outcome compared between studies was an
assessment
of the efficacy of PRP in treating pain using a visual analog
scale (VAS)
for pain.26,42–49 Secondary outcomes included adverse
reactions,
radiographic imaging of the joint space, patient
satisfaction,42,48,49 and
measures of joint function using: Foot and Ankle Disability
Index,42

Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot
scale,
the Self-Administered Foot Evaluation Questionnaire (SAFE-
Q),43
American Orthopaedic Foot & Ankle Society scale
(AOFAS),44,45 Visual
Analog Scale (VAS) for function,49 Mayo Wrist Score,26
Disabilities of
the Arm, and Shoulder and Hand (DASH).26,47
2.5. Statistical data analysis and synthesis
RevMan 5.3.5 (Cochrane Collaboration) software package was
uti-
lized for all statistical analysis in this study. Only RCTs were
included in
the meta-analysis. Dichotomous variables were presented as
odds ratios
with a 95% CI. To incorporate the heterogeneity between
studies, the
authors calculated I2 and I2 > 50% was considered to be high
hetero-
geneity and warranted investigation of study details
contributing to
heterogeneity. Random-effects model was chosen. Data on pain
and
function were grouped as either short-term, defined as patient
follow-
up visits taking place less than 6 months after final treatment,
and long-
term, defined as patient follow-up visits taking place at 6
months or
more after final treatment. In the instance that no significant
difference

was found between treatment and control, an analysis was
performed
A. Evans, et al. Journal of Orthopaedics 18 (2020) 226–236
227
comparing treatment to the baseline measurements of the
treatment
group.
3. Results
3.1. Literature search
Six thousand two hundred and thirty-six results were identified
by
our search strategy. After removal of duplicates, there were
3869 un-
ique records screened by title and abstract. 12 articles
underwent full-
text review and of which 2 were excluded for being pending
studies,
and 1 was excluded being a duplicate cohort. Therefore, 9
studies were
included in the systematic review, 4 of which were included in
the
meta-analysis.26,42–49 A PRISMA flow-chart is included in
Fig. 1.
3.2. Study characteristics and findings
Study characteristics and findings are summarized in Table 1.
Of the

9 included studies, 4 were RCTs,44–46,49 and 5 were case
series.26,42,43,47,48 All included studies were published
between 2014
and 2019.4 studies were conducted in Europe,26,42,46,47 4 in
Asia,43–45,49 and 1 in North America.48
Results included the efficacy of intra-articular PRP injections
for
osteoarthritis of the hand,26,46,47 ankle,42,43 and for talar
osteochondral
lesions,44,45,49 and Sampson et al. examined the effects of
PRP on
multiple joints including the ankle.48 Controls included intra-
articular
hyaluronic acid (HA),44,49 saline,44 and corticosteroids.46 One
study
utilized a control of surgery without injections in their
examination of
PRP as an adjunct to surgery.44 Diagnosis and grading of
osteoarthritis
was established using joint-appropriate radiographic criteria and
clinical presentation (Table 1). Table 2 summarizes the
alternative
methods for PRP preparation and administration between
studies. 7
studies reported using LP-PRP, and 2 studies did not report on
the
leukocyte status of the PRP.44,45 2 studies activated PRP with
calcium
chloride,43,49 and the mean number of treatments was 2 (range:
1–4)
separated by 1–2 weeks.
3.3. Risk of Bias Assessment

Cochrane risk of bias analysis (Fig. 2) of the RCTs
demonstrated that
3 studies had a high risk of bias,45,46,49 and 1 study had a low
risk of
bias.44 All studies reported on conflicts of interest or sources
of funding,
and only 1 study reported having an author who is an industry-
related
expert advisor.26
3.4. Meta-analysis
Our meta-analysis includes 4 RCTs and shows that PRP
effectively
improves pain and function when measured at both short-term
follow-
up defined as fewer than 6 months post-treatment, and at long-
term
follow-up, defined as 6 months or longer since treatment. For
im-
proving function, when compared to control, the results show
that PRP
is superior to control in improving function at long-term follow-
up
(Fig. 3 p = 0.0004) and short-term follow-up (Fig. 4 p < 0.02).
For
improving pain, when compared to control, PRP is superior to
control at
long-term follow-up (Fig. 5 p < 0.01). Although the
improvement of
pain from PRP treatment was not significantly different from
control at
short-term follow-up (Fig. 6 p < 0.51), there was still a
significant
improvement following treatment with PRP compared to the
baseline

values at the time of treatment (Fig. 7 p < 0.00001). Significant
Fig. 1. PRISMA Flow Chart of the Literature Search.
This figure details the literature search of 7 databases from the
inception of the database until through May 31, 2019. 6236
records were screened, including 3869
unique records, 9 of which were included in the systematic
review, and 4 were included in the meta-analysis.
228
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230

heterogeneity was present in the meta-analysis of pain due to
the in-
clusion of Malahias et al., who reported values with
interquartile range,
thereby the conversion to standard deviation provided an
acknowl-
edged source of heterogeneity.
4. Discussion
4.1. Osteoarthritis of the hand and wrist
Pain and a decline of function are the most common
manifestations
of osteoarthritis in the small joints of the hands and wrists. As
in-
flammation and degeneration progresses, patients develop joint
defor-
mity and debilitating stiffness. Symptomatic control with
NSAIDs and
intra-articular corticosteroid injections has been the mainstay of
treat-
ment, but it fails to halt disease progression and many
physicians and
patients desire a method of restoring the joint integrity and
function.
Focusing on potential curative or restorative therapies, Loibl et
al. in
a 2016 small pilot study of ten patients used two injections of
PRP into
the trapeziometacarpal (TMC) joint over four weeks to treat
patients
with osteoarthritis. They found a significant (p < 0.05)

improvement
in both VAS pain and MAYO wrist scores, however, no
improvement in
functional DASH scores at six months of follow-up.26 These
results are
supported by a small 2019 study by Mayoly et al. showing that
in three
patients with severe osteoarthritis (Kellgren-Lawrence stage
four), one
PRP and mixed micro-fat preparation injection into the wrist
reached a
Minimally Clinically Important Difference (MCID) for DASH
score in all
three patients, and a MCID in VAS pain for two out of three
patients
when followed up at one year.47 Both of these studies are
limited by the
small sample size and a lack of control groups.50
Malahias et al. conducted a 2018 RCT with thirty-three patients
with grade I-III Eaton and Littler osteoarthritis of the TMC
joint, com-
paring outcomes at three and twelve months between patients
who
received two intra-articular PRP injection two weeks apart and
control
patients who received two intra-articular methylprednisolone
and li-
docaine injections two weeks apart. While patients in the
corticosteroid
and anesthetic group had good relief of pain in the first weeks,
at twelve
month follow-up, the group that received PRP had significantly
im-
proved VAS, Q-DASH and subjective satisfaction with the

procedure
when compared to controls (p < 0.025).46
The majority of guidelines for recommended treatments at this
time
are supportive and conservative. Steroid injections have shown
some
benefit, and therefore many physicians use them as a
cornerstone of
their practice.51 However, while they provide symptomatic
relief, there
are drawbacks including a short-lasting effect and several
relative
contraindications including diabetes mellitus and
immunosuppres-
sion.52
4.2. Osteoarthritis of the foot and ankle
While estimates of the rates of osteoarthritis of the feet and
ankles
vary widely, a review of the literature by Murray et al.
demonstrated
that around 5% of adults over the age of 50 had osteoarthritis in
their
ankles.53 As weight bearing becomes painful, the quality of life
for these
patients is greatly affected. Fukawa et al., in a case series of 20
patients,
demonstrated the efficacy of three PRP injections into the
ankles se-
parated by two-week intervals. The patients had significantly
improved
pain and function scores by JSSF, VAS and SAFE-Q (P = 0.04)
at 24
weeks post treatment, although pain reduction peaked at 12

weeks.43
When comparing PRP versus HA injections, a 2012 RCT found
that PRP
was significantly better than HA for treatment of osteochondral
lesions
of the talus, with superior improvement in pain and function at
6
months.49 A 2017 retrospective study by Repetto et al. found
that at 17
months, patients who received four intra-articular PRP
injections over
the course of four weeks, had a significant reduction in VAS
with a
positive effect on function (p < 0.001), and 80% of patients
were
satisfied or very satisfied.42
The effects of PRP have also been evaluated in patients who
have
had surgery. Two studies published examined the effects of PRP
in
patients who received microfracture surgery of the talus. In
2015,
Guney et al. published a RCT containing 35 patients that
showed intra-
articular PRP provided improvement in functional status (p =
0.001)
and VAS pain (p = 0.001) at 16 months, despite having controls
who
had significantly less pain at baseline (p = 0.014).54 Görmeli et
al., in
Fig. 2. Cochrane Risk of Bias Assessment of Randomized
Controlled Trials.
Four studies assessed for bias included 3 studies with high risk

of bias, and 1
study with low risk of bias.
Fig. 3. Random effects forrest plot comparing PRP and control
for function at long-term follow-up.
231
2015, in a RCT of 40 patients, also examined PRP after
microfracture
repair of talar osteochondral lesions, where they compared
adjunct PRP
versus HA versus saline intra-articular injections and found that
PRP
resulted in the greatest subjective improvement in functional
status in
addition to the greatest reduction in VAS pain (p < 0.005) at
average
15-month follow-up.44
Other attempts at using PRP in conjunction with biologic
molecules
include a 2016 study by Sampson et al. who showed that in 125
pa-
tients, eight weeks after initial injection of autologous bone
marrow
aspirate, PRP injection resulted in a significant decrease in VAS
pain
scores at twenty weeks follow-up. However, the effect was less
pro-
nounced in non-weight bearing joints …

Contents lists available at ScienceDirect
Journal of Orthopaedics
journal homepage: www.elsevier.com/locate/jor
Case Report
Clinical outcomes following injections of leukocyte-rich
platelet-rich plasma
in osteoarthritis patients
Masahiko Kenmochia,b,∗
a Kenmochi Orthopedic Surgery Sports Clinic, KOSSMOS
Medical Corporation, 42-1 Higashi-honcho, Ota, Gunma
Prefecture, Japan
b Department of Orthopaedic Surgery, Kyorin University,
Tokyo, Japan
A R T I C L E I N F O
Keywords:
Knee osteoarthritis
Leukocyte-rich platelet-rich plasma
Knee injury and osteoarthritis outcome score
Outcome measures in rheumatology-
osteoarthritis research society international
Magnetic resonance imaging osteoarthritis
knee score
Bone mallow lesion
Multiple injection
A B S T R A C T

Background: Scientists are trying to discover how to repair
cartilage defects in knee osteoarthritis (KOA). In our
previous study, we found a fibrocartilage-rich cover over the
defective portions of cartilage after administering
leukocyte-rich platelet-rich plasma (LR-PRP). This study aimed
to investigate the efficacy of multiple injections
of LR-PRP for the treatment of KOA and determine an LR-PRP
treatment protocol for KOA in actual clinical
practice.
Hypothesis: We hypothesized that using abundant LR-PRP
would improve outcomes in patients with KOA.
Study design: Prospective, cross-sectional, interventional,
randomized trial.
Methods: Intra-articular LR-PRP injections were administered
to 50 knees. Patients received six injections of LR-
PRP in total, which were administered at 4-week intervals.
Patients were evaluated based on clinical outcomes,
including visual analog scale (VAS) scores, Knee injury and
Osteoarthritis Outcome Scores (KOOS), and magnetic
resonance images (MRI) and radiographic findings before
treatment and at 3 and 6 months after treatment. We
investigated the recurrence of pain and presence/absence of
MRI changes. Furthermore, we examined the
Outcome Measures In Rheumatology-Osteoarthritis Research
Society International (OMERACT-OARSI) re-
sponder criteria.
Results: The mean improvement rate, as assessed by VAS, was
61.6% (P < .0001). Concerning OMERACT-
OARSI, 37 of 50 knees (74%) were considered responders.
There was a significant difference in the follow-up
MRI findings, as assessed by the MRI Osteoarthritis Knee Score
for bone marrow lesions (P < .007). No sig-
nificant difference in osteoarthritis grade was observed.
Conclusion: Our LR-PRP procedure resulted in 74% of knees
being classified as responders, regardless of the

degree of knee deformation. Multiple injections of LR-PRP was
effective for advanced grades of KOA. Thus,
based on the results of our study, we believe that LR-PRP
should be implemented as an additional conservative
treatment option for non-operative management of OA.
Trial registration: Japan Medical Association Center for
Clinical Trials (JMA-XXX).
What is known about the subject: Recent reports suggest that
leukocyte-rich platelet-rich plasma (LR-PRP) may be beneficial
for long-
term relief of osteoarthritis (OA) symptoms.
What this study adds to existing knowledge: Our LR-PRP pro-
cedure was effective in patients with knee OA, regardless of the
degree
of knee deformation. Therefore, we suggest that LR-PRP
injections
should be added as an additional conservative treatment option
for
management of OA.
1. Introduction
Osteoarthritis (OA) is a multifactorial chronic condition
characterized by the destruction of articular cartilages, which
leads to
joint space loss.1 Significant efforts are being made by
scientists to
discover how to repair cartilage defects in knee OA (KOA).
There are
several operative (microfracture, osteochondral, and tissue
engineered
grafts) and non-operative (single-molecule agents, hyaluronic
acid, and

corticosteroid injections) treatment strategies for cartilage
repair and
management of KOA pain.
Currently, there is high demand for immunomodulatory
biological
approaches to treat cartilage defects and delay progressive OA.2
Reports
suggest that platelet-rich plasma (PRP) may promote healing
and im-
prove osteoarthritis (OA) symptoms for a longer duration.3
Cartilage
regeneration using synovial stem cells has also been reported.4
Multiple
https://doi.org/10.1016/j.jor.2019.11.041
Received 31 October 2019; Accepted 24 November 2019
∗ Kenmochi Orthopedic Surgery Sports Clinic, 42-1 Higashi-
honcho, Ota City, Gunma Prefecture, Japan.
E-mail address: [email protected], [email protected]
Journal of Orthopaedics 18 (2020) 143–149
Available online 27 November 2019
0972-978X/ © 2019 The Author(s). Published by Elsevier B.V.
on behalf of Professor P K Surendran Memorial Education
Foundation. This is an open access article
under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
injections of PRP have an anti-inflammatory effect on the
synovium in a
short period of time, this effect lasts for a long time and has a
cartilage

protective effect. However, there are basic research reports that
this
effect cannot be seen with a single injection.5 We previously
found on
arthroscopy that cartilage defects were covered with rich
fibrocartilage
after 7 months of treatment with leukocyte-rich platelet-rich
plasma
(LR-PRP) and PRP (Fig. 1). There is also a similar basic
research report
supporting this findings.6
Although PRP treatment is said to be effective for OA patients
with
low-grade inflammation,7 as per the Kellgren-Lawrence (K-L)
classifi-
cation,8 a large proportion of patients with clinical OA with
severe pain
are those with advanced-grade inflammation. Based on reports
that
multiple injections may be effective for advanced-grade
inflammation7
and the fact that formation of rich fibrocartilage was noted after
about
6 months (as described above), injections were administered six
times
every 4 weeks for 6 months. Therefore, we hypothesized that
abundant
LR-PRP may cause fibrocartilage-rich cover over the defective
portion
of the cartilage in KOA patients with advanced-grade
inflammation.
In this study, we investigated the efficacy of multiple injections
of

LR-PRP for treatment of KOA. Moreover, we determined an
LR-PRP
treatment protocol for KOA in actual clinical practice.
2. Method
This was a prospective, interventional, clinical trial. It was
approved
by the Institutional Ethics Review Board of the Japanese
Association for
the Promotion of State of Art in Medicine Ethics Review
Committee
(Approval no.: KE-06). In addition, the study was conducted in
ac-
cordance with the law for ensuring the safety of regenerative
medicine,
after examination by specific committees and authorization by
the
Ministry of Health Labor and Welfare for the use of
regenerative
medicine.9 This study was registered in the clinical trial
registry of the
clinical Japan Medical Association Center for Clinical Trials
(JMA-
IIA00351). This study was conducted between June 2018 and
April
2019.
2.1. Patient selection
Subjects for this treatment were recruited using advertisements
on
homepages and social networking services, radio broadcasting,
health
magazines, and in-clinic posters. All patients with a diagnosis

of KOA
were screened. All patients provided written informed consent
after
receiving an explanation of the potential benefits of PRP, the
treatment
procedure, and follow-up.
The inclusion criteria were: 1) long-standing difficulties in per-
forming activities of daily living, and 2) a desired level of
activity that
could not be reached despite continued treatment with
hyaluronic acid
injections, steroid injections, and/or NSAIDs at various clinics
and
hospitals. The exclusion criteria were: 1) a history of a systemic
dis-
order, such as rheumatoid arthritis, malignant cancer,
haematological
disease, infection, or immunodeficiencies, 2) recent intra-
articular in-
jection of corticosteroids and HA in the past 2 weeks, and 3)
recent
administration of anti-cancer drugs or immunosuppressive
drugs.
The number of patients screened and the treatment protocol are
shown in Fig. 2. Although 58 knees were screened, the
treatment was
indicated for a total of 50 knees (eight were excluded).
2.2. Processing PRP
2.2.1. Preparation of PRP (LR-PRP)
We creatively designed a preparation protocol for PRP. Based
on a

report by Shin et al.,10 we chose a method of centrifuging
whole blood
to obtain the highest concentration ratio. First, the 20-cm3
blood
samples drawn from the patients were divided into two samples
of
9 cm3 and placed in sterilized 10-cm3 glass tubes. Next, 1 cm3
of an-
ticoagulant (sodium citrate solution) was added to each tube
containing
the samples and the tube was immediately centrifuged at 1000 G
for
5 min at room temperature (Tabletop Centrifuge 2420;
KUBOTA Cor-
poration, Tokyo, Japan). The centrifugation allowed blood
separation
into three distinct layers. At the bottom of the glass tube, red
blood
corpuscles were present. At the top of the glass tube, the
acellular
plasma layer was obtained, containing circulating plasmatic
molecules
and a few platelets [platelet-poor plasma (PPP)]. Between these
two
layers was an intermediate layer with an increased platelet
concentra-
tion, representing a buffy coat. Using a sterile syringe with an
18-gauge-
long needle, the PPP, buffy coat with PRP, and some red blood
cor-
puscles were aspirated (i.e., the upper and middle layers were
collected
after centrifuging) from both samples and collected into one dry
glass
tube without anticoagulant. This tube was then centrifuged at
1500 G

for 15 min at room temperature. This second centrifugation
again al-
lowed the blood to separate into three distinct layers, with a
platelet
concentrate at the bottom of the tube. The PPP on the top was
aspirated
and discarded, leaving just enough serum to maintain the buffy
coat as
a middle layer and thin red blood corpuscles as a bottom layer.
The
glass tubes were then gently shaken to obtain ready-to-use PRP.
We
obtained approximately 2.4 cm3 of PRP from 20 cm3 of blood
per in-
jection (Fig. 3). Three 10 cc glass tubes and two syringes were
used per
injection.
2.2.2. PRP injection
Six ultrasonography (US)-guided intra-articular injections were
ad-
ministered to every patient by a well-trained doctor (not
involved in
outcome assessment) at 4-week intervals.
During the procedure, the patient's knee was kept in a slight
bent
position at about 20°, and the injection was administered in a
sterile
condition using a 25-G needle via a suprapatellar approach from
the
outside of the knee with US guidance (SonoSite iViz®; Fuji
Film
SonoSite Inc., Tokyo, Japan).

In cases of knee effusion, the suprapatellar pouch of the knee
was
Fig. 1. Fibrocartilage-rich cover over the defective portion of
the cartilage.
(a) Medial femoral condyle before treatment; (b) Arthroscopic
findings 7
months after PRP treatment.
PRP, platelet-rich plasma.
M. Kenmochi Journal of Orthopaedics 18 (2020) 143–149
144
Fig. 2. Patient follow-up.
MRI, magnetic resonance imaging; X–P, radiographic findings;
KOOS, Knee Injury and Osteoarthritis Outcome Score; PRP,
platelet-rich plasma.
145
observed, and the joint fluid was aspirated as much as possible,
while
confirming the presence or absence of the accumulation of
synovial
fluid (Fig. 4). Next, the suction syringe was replaced with a
PRP syringe
and about 2.4 mL of PRP was gently and smoothly injected.
2.3. Generation of platelet concentrates and haematology

measurements
During the preparation of PRP using the abovementioned
protocol,
each residue sample prepared under the same conditions was
examined
using a haemocytometer (Microsemi LC-66; HORIBA Ltd.,
Kyoto,
Japan). To avoid platelet activation, the measurement of
samples was
performed at room temperature as soon as possible after loading
the
haemocytometer chamber. The results from the analysis were
assessed
based on the PAW classification, which classifies PRP
according to
platelet count, activation, and white blood cell count,11 and the
Mishra
Sports Medicine PRP classification system, which classifies
PRP ac-
cording to the same criteria as the PAW.12
Fig. 3. Preparation of PRP (LR-PRP)
We modified the standard procedure for obtaining PRP and
obtained approximately 2.4 cm3 of PRP
PRP, platelet-rich plasma; LR-PRP, leukocyte-rich platelet-rich
plasma; PPP, platelet-poor plasma.
146
2.4. Treatment and evaluation

After administration of injections, the patients did not have any
restrictions and were allowed to resume activities of daily
living.
Patients were clinically evaluated via subjective and objective
assess-
ments using KOOS and VAS at baseline and at 12- and 24-
weeks post-
treatment to determine the primary clinical outcomes of PRP
treatment.
After 12 and 24 weeks, radiographic imaging and MRI were
performed.
Demographic and clinical characteristic data, including patient
age,
sex, race, OA grade according to the K-L classification, and
body mass
index (BMI), were measured in all patients. Regression analysis
was
performed to identify variables that affected treatment response,
such
as OA grade, BMI, age, and preoperative pain. In addition, the
corre-
lations between the leukocyte concentration rate and treatment
out-
come and between the platelet concentration rate and treatment
out-
come were analysed. To investigate the number of times PRP
should be
administered, we examined the average number of doses
required to
reduce the pain by 20% and 50% or more. A visual analogue
scale
(VAS) ruler was used to evaluate pain and determine
improvement. The
VAS used a scale of 0 mm–100 mm, with 0 mm representing no

pain
and 100 mm representing the worst possible pain to quantify
subjective
pain.
The Outcome Measures In Rheumatology-Osteoarthritis
Research
Society International (OMERACT-OARSI) responder's
criteria13 was
used to determine treatment effect (Fig. 5).
2.5. Clinical assessment
Clinical assessments included the following: 1) knee injury and
os-
teoarthritis outcome scores (KOOS) including KOOS-total (T),
symp-
toms (S), pain (P), activity (A), sports (Sp), and quality of life
(Q)14; 2)
VAS scores15; 3) radiographic findings; and 4) MRI (0.3 T
open-type
instrument; HITACHI Medico Airis Bent, Tokyo, Japan)
findings. The
bone marrow lesion (BML) area was assessed on MRI using the
MRI
Osteoarthritis Knee Score (MOAKS).16 The MOAKS BML is
scored for 15
regions (two patellar, six femoral, and seven tibial) based on
BML size
(none = 0; < 33% of region = 1; 33–66% of region = 2; > 67% =
3)
for a maximum score of 15 × 3 = 45 per knee. In addition, the
nature,
duration, and severity of any adverse events related to this
study pro-
tocol was assessed.

2.6. Statistical analyses
Continuous data are reported as the mean ± standard deviation
(SD). Welch's t-tests were performed for group comparisons,
and paired
t-tests were performed to evaluate within-group changes. All
statistical
analyses were performed using SPSS version 22.0 for Windows
(IBM
Corp., Armonk, NY). A P-value of ≤0.05 was considered
statistically
significant.
Fig. 4. PRP injection technique with ultrasonography guidance
(a) Inspection probe and ruler; (b) On the screen, a 21-G needle
is inserted in the suprapatellar capsule in a parallel projection;
(c) PRP injection is performed
ensuring there is no resistance.
PRP, platelet-rich plasma.
Fig. 5. OMERACT-OARSI flow chart (50 knees)
Details of responders (Grade 1: 4/4; Grade 2: 5/8; Grade 3:
17/23; Grade 4: 11/15).
OMERACT-OARSI, Outcome Measures In Rheumatology-
Osteoarthritis Research Society International.
147
3. Results
The average age of the patients (six men and 38 women) was

67.2 ± 9.6 years (range, 36–84 years), and the average BMI was
25.3 kg/m2(19.6–33.8). There were 42 Japanese and two
Brazilian
patients. There were 22 cases of left KOA and 28 of right KOA.
Thus,
there were six patients with OA in both knees. The degree of
KOA ac-
cording to the K-L classification was Grade I in four knees,
Grade II in
eight knees, Grade III in 23 knees, and Grade IV in 15 knees.
For the PRP used in this study, the mean platelet concentration
was
4.8-fold that in whole blood, and the mean white blood cell con-
centration was 2.6-fold that in whole blood. Hence, the overall
average
LR-PRP classification according to MISHRA was Type 1-B and
P3-Aα
according to PAW.
The mean improvement rate as per the VAS was 61.6%
(P < 0.0001). The average VAS scores before treatment and
after each
PRP injection were as follows: 5.8 cm (before treatment), 48
mm (after
first injection), 44 mm (after second injection), 41 mm (after
third in-
jection), 34 mm (after fourth injection), 30 mm (after fifth
injection),
and 31 mm (after sixth injection). VAS scores significantly
improved
after the first injection in Grade II patients (P = 0.0053) and
after the
second injection in Grade III and IV patients (P = 0.0039 and
P = 0.0003, respectively). There were 47 knees (94%) with
≥20%

improvement in VAS scores. On an average, 2.3 doses were
required for
a 20% improvement. Similarly, there were 37 knees (74%) with
≥50%
improvement in VAS scores. On average, 3.5 doses were
required for a
50% improvement. On average, 4.8 doses were required for the
highest
improvement in VAS score, depending on the OA grade as per
the K-L
classification: K-L Grade I, 4.5; K-L Grade II, 5.1; K-L Grade
III, 4.5; K-L
Grade IV, 5.0.
The improvements in mean KOOS at baseline and at the 3- and
6-
month follow-ups were as follows: KOOS-T: 56.2 to 65.1 to
69.1;
KOOS–S: 55.3 to 65.9 to 70.1; KOOS–P: 53.6 to 63.4 to 70.2;
KOOS-A:
68.3 to 76.6 to 79.1; KOOS-Sp: 33.7 to 41.6 to 46.0; KOOS-Q:
34.4 to
48.7 to 50.9 (all P < 0.01). There were significant differences in
KOOS
(all P < 0.0001), including KOOS-Sp (before vs. 3 months, P =
0.005).
There was no correlation between age and VAS score
improvement
rate (r = 0.134, P = 0.125), or between BMI and VAS score im-
provement rate (r = −0.055, P < 0.0001). Similarly, no
correlation
was found between the concentration of leukocytes (r = 0.153,
P < 0.0001) and platelets (r = −0.135, P < 0.0001).
According to the OMERACT-OARSI, responses were observed

in 37
knees (74%), and no response was observed in 13 knees (26%)
(Fig. 5).
There were no obvious adverse events. However, discomfort and
pain
around the knee joint occurred in 39 of 50 patients (58%) and
dis-
appeared within a few days.
Follow-up MRIs and radiographic imaging were performed at 3
and
6 months after treatment. There were no cases where deformity
was
aggravated on radiographic findings. The mean grade of BMLs
as per
the MOAKS classification was 7.44 before administration, 7.22
after 3
months, and 6.6 after 6 months. Significant changes occurred in
BML
between pre-treatment and after 3 months (P = 0.040), between
pre-
treatment and after 6 months (P = 0.0070), and between 3
months and
6 months (P = 0.020). In contrast, no significant differences in
os-
teoarthritis grade was observed.
4. Discussion
This study found that the mean improvement rate following LR-
PRP
therapy, as measured by VAS, was 61.6% (P < 0.0001).
Furthermore,
there were significant differences in all subsections of the
KOOS, and
according to the OMERACT-OARSI, 37 knees (74%) were

responsive
and 13 knees (26%) were not (Fig. 5). On follow-up MRIs,
significant
changes occurred in BML. In contrast, no significant
differences in os-
teoarthritis grade were observed.
PRP treatment reports vary depending on the components of
PRP.
We believe that remodelling by macrophages is essential for the
repair
of the degenerating knee joint cartilage with a cartilage defect.
Accordingly, based on a report by Shin et al.,10 we chose a
method of
centrifuging whole blood to obtain the highest concentration
ratio.
However, despite maintaining the surrounding conditions and
using
samples from the same person, the finished PRP had a different
con-
centration each time. Likewise, even when a commercially
available
separation kit was used, it was still difficult to achieve the same
PRP
concentration each time, as the effects of environmental
variables in-
fluence the outcome.17,18 However, considering that we are
using
human blood samples, such variations are inevitable.
Most patients showed significant changes (pre-treatment and
post-
treatment) in VAS scores and KOOS. There was no clear
significant
difference between severity of deformity and treatment

outcome, and
good treatment results were confirmed even when the K-L
classification
grade was advanced. Based on our purified LR-PRP preparation
and
administration method, LR-PRP administration shows promise
as a
temporary treatment for many OA patients. There are large
variations
in the literature regarding the dosing schedule of PRP injections
for
KOA.19–22
In a previous study, we were surprised to find that cartilage
defects
were covered with rich fibrocartilage on arthroscopy after 7
months of
treatment with LR-PRP and PRF. Hence, we hypothesized that
abundant
LR-PRP may cause a fibrocartilage-rich cover over the
defective portion
of the cartilage and abundant PRP and long-term administration
would
be effective for advanced KOA, as it was for cartilage defects.
This
findings may be thought of as supporting Fang's et al. report.6
With regard to our administration method, referring to previous
reports,23 we decided to administer six injections at 4-week
intervals.
Based on our results, we determined whether we should have
ad-
ministered PRP over a longer or shorter duration. To reach 50%
or more
patient satisfaction with regard to degree and symptom
improvement,

four injections or more appeared to be necessary. In our study,
the
number of doses required for an improvement rate of 20% and
50%,
and maximum improvement were significantly increased.
Therefore,
the more frequent the administration, the better the recovery of
pain.
Some reports have elucidated the efficacy of multiple PRP
injections
and one study reported the effectiveness of multiple PRP
injections for
low grade KOA.5 Cook et al.20 reported that patients with more
severe
KOA need four, five, or six injections to get maximal relief.
The results
of our research strongly support their findings.
According to some reports,24,25 bone marrow oedema on MRI
is
considered to be caused by a cortical break. In our study, there
were
significant differences in MRI findings before and after 6
months. These
findings suggest the restoration of a cortical break for 6 months.
Therefore, we can assume that the exposed part of the
subchondral
bone is covered for 6 months. Temporary covering of cartilage
defects
with fibrocartilage and prevention of subchondral bone
exposure are
believed to lead to an improvement in pain and function.
4.1. Limitations
This study had several limitations. The cleanliness level at our

hospital's PRP production site corresponded to class 10000 of
the NASA
standard. We worked in a clean environment, but the PRP
preparation
method used in this study was the open technique. Accordingly,
the
contamination risk may have been increased.
Compositional variation was believed to be not only due to
home-
ostasis, but also the preparation procedure. Therefore, future
studies
with more precise efforts regarding the accuracy of the method
are
required.
Next, the single-centre design and low number of cases, the lack
of a
placebo control group, and a rather short-term follow-up limits
the
statistical strength of our conclusions. Therefore, we will
consider in-
cluding a placebo group in future studies. Although this study
did not
include a control group and does not have significant statistical
power,
148
the results indicate real-world evidence, and they warrant
further va-
lidation in future studies.

In conclusion, the results of our PRP procedure was
satisfactory,
regardless of the degree of knee deformation. PRP is a source of
auto-
logous and safe growth factors and has the potential to cause a
para-
digm shift in conservative treatment protocols for knee
osteoarthritis. It
can improve subjective pain and KOOS results. Therefore, we
suggest
that PRP should be administered in the clinical setting as an
additional
conservative treatment option for KOA patients before
considering
TKA.
Unblinded ethical approval statement
This was a prospective, interventional, clinical trial. It was
approved
by the Institutional Ethics Review Board of the Ministry of
Health Labor
and Welfare (approval no.: KE-06).
Unblinded clinical trial registration statement
This study was registered in the clinical Japan Medical
Association
Center for Clinical Trials (JMA-IIA00351).
Author contributions
The author, Masahiko Kemmochi, contributed to the conception
and
design of the study, or the acquisition of data, or the analysis

and in-
terpretation of data.
The author, Masahiko Kemmochi, contributed to the drafting of
the
article or revising it critically for important intellectual content.
The author, Masahiko Kemmochi, approved the approval of the
final
version of the manuscript to be submitted.
Role of the funding source
The study sponsors had no involvement in this research.
Ethics approval of research on humans
This prospective interventional clinical trial was approved by
the
Institutional Ethics Review Board of the Ministry of Health
Labor and
Welfare (approval no.: KE-06). All patients provided written
informed
consent after receiving an explanation about the potential
benefits of
PRP, the treatment procedure, and follow-up.
Data availability
The data is available from Masahiko Kemmochi upon
reasonable
request.
Declaration of competing interest
The author declares that there are no conflicts of interest.

Acknowledgments
None.
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Osteoarthritis
SUPPLEMENT
Intraarticular Platelet-Rich Plasma
Injection in the Treatment of
Knee Osteoarthritis
Review and Recommendations
ABSTRACT
Pourcho AM, Smith J, Wisniewski SJ, Sellon JL: Intraarticular
platelet-rich plasma
injection in the treatment of knee osteoarthritis: review and
recommendations. Am
J Phys Med Rehabil 2014;00:00Y00.
Intraarticular platelet-rich plasma (PRP) injection has emerged
as a promising
treatment for knee osteoarthritis. Studies to date, including
multiple randomized
controlled trials, have shown that PRP is a safe and effective
treatment option for
knee osteoarthritis. Intraarticular PRP is similar in efficacy to

hyaluronic acid, and
seems to be more effective than hyaluronic acid in younger,
active patients with
low-grade osteoarthritis. Treatment benefits seem to wane after
6Y9 mos. There
are numerous PRP treatment variables that may be of
importance, and the optimal
PRP protocol remains unclear. Future investigations should
control and analyze
the effects of these variables in PRP treatment. High-quality
randomized controlled
trials are needed to optimize PRP treatment methods and better
define the role of
PRP in osteoarthritis management in the knee and, potentially,
in other joints.
Key Words: Knee, Osteoarthritis, Platelet-Rich Plasma,
Regenerative Medicine, Injections
BACKGROUND
Osteoarthritis (OA), also known as degenerative arthritis or
osteoarthrosis, in-
volves mechanical and biologic abnormalities of the articular
cartilage
and subchondral bone.1 OA affects approximately 250 million
people (nearly 27
million Americans), and the prevalence is expected to rise as
life expectancy
increases.2,3 OA causes moderate-to-severe disability in more
than 43 million
people globally, and nearly one in every two people may
develop symptomatic
knee OA by the age of 85 yrs.4,5 Once articular cartilage is
damaged, healing
potential is poor, leading to focal cartilage lesions and OA.6
Given the prevalence

of OA and the morbidity associated with it, any treatment that
may help alleviate
the symptoms, improve function, and ideally reverse the damage
and promote
healing, is of interest to both patients and medical specialists.
The ongoing search
for effective nonoperative OA treatments has driven the interest
in Bregenerative[
biologic therapies.7 In the last decade, intraarticular platelet-
rich plasma (PRP)
injection has emerged as a promising treatment option for OA.8
Authors:
Adam M. Pourcho, DO
Jay Smith, MD
Stephen J. Wisniewski, MD
Jacob L. Sellon, MD
Affiliations:
From the Departments of Physical
Medicine & Rehabilitation (AMP, JS,
SJW, JLS) and Radiology and Anatomy
(JS), Sports Medicine Center, Mayo
Clinic, Rochester, MN.
Correspondence:
All correspondence and requests for
reprints should be addressed to:
Jacob L. Sellon, MD, Department of
Physical Medicine & Rehabilitation,
Sports Medicine Center, Mayo Clinic,
W14 Mayo Building, 200 1st St SW,
Rochester, MN 55905.
Disclosures:
Financial disclosure statements have

been obtained, and no conflicts of
interest have been reported by the
authors or by any individuals in control
of the content of this article.
0894-9115/14/0000-0000
American Journal of Physical
Medicine & Rehabilitation
Copyright * 2014 by Lippincott
Williams & Wilkins
DOI: 10.1097/PHM.0000000000000115
www.ajpmr.com PRP Injection as a Treatment for Knee OA 1
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized
reproduction of this article is prohibited.
PRP is most simply defined as a volume of
plasma that has a platelet (PLT) count above baseline
(BL) blood levels.9 PRP is an autologous blood
product that can be injected into damaged areas to
deliver PLT-derived growth factors (GFs) and pro-
mote healing.10 The autologous nature of PRP the-
oretically reduces the risk of potential side effects
and makes it an attractive treatment option.11,12
Numerous studies have demonstrated PRP
efficacy in the treatment of chronic tendinopathy
and ligamentous injuries.13Y19 The most compelling
data to date have been in elbow lateral epicondylitis
(i.e., Btennis elbow[), for which multiple random-
ized controlled trials have demonstrated therapeu-
tic benefit.20Y22 In the past several years, a growing

body of evidence has accumulated examining PRP
as a possible treatment of knee OA. This review
outlines the many variables involved in the use of
PRP, summarizes the currently available literature
on its application in knee OA, and suggests avenues
for further research.
VARIABLES IN PRP TREATMENT
When using PRP as a treatment for OA, there
are many variables to consider (see Table 1).78
These include preparation method, needle gauge for
blood harvest and injection, PLT concentration,
PLT granule secretion variability, leukocyte (and
subtype) concentration, PLT storage, anticoagulant
use, PLT preactivation, local anesthesia use, image
guidance use, injection volume, injection frequency,
preinjection and postinjection protocol, severity of
OA being treated, and other patient factors. An un-
derstanding of these variables is essential in criti-
cally analyzing the literature and deciding how to
implement PRP treatment into clinical practice.
Preparation Method
The first variable to consider when using PRP
is the method of preparation (Figs. 1AYC). Most
methods use either a centrifuge or density gradient
cell separator to separate whole blood into its cel-
lular components.23,24 Typically, the initial Bspin[
separates the red blood cell and buffy coat/plasma
(leukocyte and PLT) layers, whereas a second spin is
used in some systems to further concentrate PLTs.
Therefore, the number of centrifugations and cen-
trifuge speed/timing has a major influence on the
final PRP concentration of PLTs and leukocytes.25

Because of these variables, manual laboratory prep-
aration can be technically demanding and difficult to
precisely reproduce. Commercially available systems
theoretically provide more precision, but variation
among systems complicates comparisons.23,26,27
Needle Gauge for Blood Harvest
and Injection
Needle gauge is another factor that may po-
tentially affect PRP. Smaller gauge needles used
in blood draws can cause premature activation of
PLTs.28 Because PLTs release 90% of their GFs
within 10 mins of activation, needle gauge may
affect the timing of GF release.29 To avoid un-
intentional activation of PLTs, clinicians may con-
sider using large bore needles (21-gauge or larger)
and slow aspiration during blood harvest. It is
unclear whether needle gauge is an important factor
during PRP administration. Clearly, further research
is needed to determine the effects of specific needle
gauges on PLT activation in the context of PRP
preparation and injection.
PLT Concentration
PLT concentration may be arguably one of the
most important variables in PRP treatment. Mishra
et al. 30 proposed a PRP classification system with
subcategories of relatively high (95� BL) and low
(G5� BL) PLT concentrations. However, PLT con-
centration in the published literature on knee OA
has been variable and inconsistently reported. Some
authors suggest that PRP PLT concentration should

be at least two times the whole blood PLT concen-
tration; however, concentrations up to eight times
of blood levels have been reported with good re-
sults.23,31 There is in vitro evidence that PRP with
higher PLT concentration (4.69�) releasesmore GFs
than PRP with lower concentration (1.99�).32 Other
laboratory studies have suggested a ceiling effect of
TABLE 1 Variables in PRP treatment
Preparation method
Needle gauge for blood harvest and injection
Platelet concentration
Platelet granule secretion (e.g., GFs)
Leukocyte (and subtype) concentration
Platelet storage (vs. immediate injection)
Anticoagulant use
Platelet preactivation
Local anesthetic use
Palpation vs. image guidance
Injection volume
Injection frequency
Preinjection and postinjection protocol (e.g., NSAID/
activity restriction)
Type and severity of disease being treated
Patient-specific factors (e.g., age, sex, platelet disorders)
2 Pourcho et al. Am. J. Phys. Med. Rehabil. & Vol. 00, No. 00,
Month 2014

the anabolic effects of PLT concentration.33Y36 In
practice, there is evidence that positive clinical out-
comes in knee OA can be obtained with relatively low
PLT concentrations (2Y3� BL).25,37Y40 Scientific ev-
idence is currently limited with regard to optimal
PRP PLT concentration for the treatment of knee
OA and requires further investigation.
PLT Granule Secretion
One of the most unpredictable variables in PRP
injection is PLT granule secretion. PLT granules
release a variety of GFs, including PLT-derived GF,
transforming GF beta, insulin-like GF-1, and epi-
dermal GF. The concentrations of these GFs may
vary between patients and within the same patient
at different times.10 These molecules are believed
to be important in maintaining joint homeostasis,
tissue healing, and tissue regeneration.10 In addi-
tion, PLT granules store substances such as aden-
osine diphosphate, adenosine triphosphate, histamine,
dopamine, serotonin, cathespin D, cathespin E, elas-
tases, and hydrolases, which are believed to play a
complex role in tissue regeneration.10,12,41 The sig-
nificance of variability in PLT granule secretion on
PRP treatment is unknown and would be difficult to
account for in clinical trials.
Leukocyte (and Subtype) Concentration
The presence or absence of leukocytes and their
subtypes may also play an important role in PRP
treatment efficacy. Mishra et al’s30 PRP classification
defined leukocyte-rich (LR) as Bincreased over
baseline[ and leukocyte-poor (LP) as Bminimal to no

leukocytes.[ For most currently available PRP sys-
tems, leukocyte concentration is directly related to
PLT concentration.26 Although there are a few ex-
ceptions, most systems produce either an LR-PRP
with a relatively high PLT concentration (95� BL) or
an LP-PRP with a relatively low PLT concentration
(G5� BL). In vitro human and animal research has
shown that LR-PRP yields higher GF concentrations
than LP-PRP, but LR-PRP also contains more cata-
bolic/inflammatory cytokines.32,42 In vivo research in
various tissue types has shown that LR-PRP causes a
significantly greater acute inflammatory response at
5 days after injection when compared with LP-PRP,
with no significant difference in the inflammatory
response or cellularity at 14 days.43 Studies of
intraarticular PRP injections in arthritic knees have
supported this finding.44 Interestingly, there is evi-
dence that LR-PRP has both proinflammatory and
anti-inflammatory properties.45 Intuitively, one
could surmise that an LR-PRP product would be
more beneficial in chronic conditions, which may
benefit from some degree of inflammation, whereas
an LP-PRP product would bemore beneficial in acute
or subacute conditions, where additional inflamma-
tion may be detrimental. With regard to knee OA,
positive clinical results have been reported using
both LR-PRP and LP-PRP intraarticular injec-
tions.25,38 One study comparing LR-PRP and LP-PRP
yielded similar efficacy, although the LR-PRP group
had a higher incidence of postinjection pain.25
FIGURE 1 PRP preparation: (A) typical PRP centrifuge. After
harvest, autologous whole blood is centrifuged to
separate and concentrate platelets. This particular single-spin
PRP centrifuge can process four
samples simultaneously in approximately 5 mins. (B) Top layer

(PRP) is aspirated from the bottom
syringe into the top syringe of a Bdouble syringe[ system.
Unused bottom layer is rich in red and white
blood cells. (C) On the left, the final PRP product is ready for
injection. On the right, the unused
remaining blood products remain in the bottom syringe.
Therefore, it is unclear whether leukocyte concen-
tration has a significant effect on PRP injection effi-
cacy in knee OA.
Regarding leukocyte subtypes, there is evi-
dence that polymorphonuclear neutrophils (PMNs)
may have a negative effect on cartilage.10,46 PMNs
infiltrating injured tissue can exacerbate or increase
the original tissue damage.47Y49 Theoretically, LP-
PRP products may be preferable in the treatment of
knee OA because of their very low concentrations of
PMNs. However, typically, LR-PRP is relatively low in
PMNs, and some have postulated that these concen-
trations are not high enough to cause significant
inflammatory reaction.26 Therefore, the optimal
PMN level in PRP injection for knee OA is unknown.
PLT Storage
The use of freeze-thawing to produce PLT
releasate/lysate vs. the immediate injection of PRP
after preparation is another point of contention.

When serial PRP injections are performed, freeze-
thawing provides the advantage of a single blood
draw. However, many GFs have short half-lives, and
there is some evidence that freeze-thawing lowers
GF concentrations.27 Nevertheless, this technique
has been used in multiple trials demonstrating
clinical benefit in patients with knee OA.25,44,50,51
Therefore, the clinical implications of freeze-
thawing on PRP injection efficacy are debatable.
Anticoagulant Use
Anticoagulation of PRP is another potential
treatment variable. Most commercial PRP systems
recommend use of an anticoagulant to prevent
premature clotting after harvest. One study found
that acid citrate dextrose and citrate-theophylline-
adenosine-dipyridamole were superior to heparin
and sodium citrate in maintaining the integrity of
PLT structures and preventing the PLT spontane-
ous activation.52 Furthermore, PRP prepared with
acid citrate dextrose or citrate-theophylline-
adenosine-dipyridamole released more transforming
GF beta and enhanced proliferation of humanmarrow
stromal cells compared with PRP prepared using
heparin or sodium citrate as anticoagulants.52 Thus,
the limited evidence to date suggests that acid
citrate dextrose or citrate-theophylline-adenosine-
dipyridamole may be preferable anticoagulants for
PRP preparation.
PLT Preactivation
PRP preactivation is controversial. Preactivation
is the administration of a substance to promote PLT

release of GFs and other substances involved in the
healing process. Clotting, although undesirable be-
fore injection, is vital for PLT degranulation after
PRP delivery.52 Therefore, when using an anticoag-
ulant, PLT activation is necessary for GF release.
Commonly used preactivation agents include calci-
um chloride (CaCl2) and thrombin. Although stud-
ies suggest that CaCl2 provides sufficient PLT
activation, there is some evidence that it causes
differentiated GF release, possibly affecting out-
comes.53,54 Preactivation with thrombin is also not
without controversy. Animalmodels have shown that
thrombin stimulates earlier GF release in the first
24 hrs compared with no preactivation.55 However,
thrombin has also been shown to inhibit PRP
osteoinductivity and, therefore, is possibly detri-
mental in knee OA.56 Notably, type 1 collagen alone
can activate PLTs after injection, providing sustained
release of anabolic cytokines.57 There is also evidence
that PLTs without preactivation stimulate wound
healing more efficiently than preactivated PLTs.58
Indeed, positive clinical results in knee OA have been
reported in PRP injections both with and without
PLT preactivation.25,40,44,50,51,59 To date, there are no
clinical trials comparing different types of PRP
activation.
Local Anesthetic Use
The use of local anesthesia for PRP injections
has also been debated. In vitro local anesthetics
have been shown to decrease the positive effects of
PRP.60 Furthermore, multiple studies have dem-
onstrated the chondrotoxicity of local anesthetics.61Y63

Given the lack of clinical data on the subject, it is
difficult to give a recommendation regarding the use
of local anesthetics with PRP therapy. However, if local
anesthesia is used before PRP intraarticular injection,
it seems reasonable to avoid injection into the joint.
Palpation vs. Image Guidance
Logically, one may expect PRP injection accuracy
to affect knee OA clinical outcomes. It is notable that
most PRP kneeOA studies to date have used palpation-
guided injections with success.25,37Y40,44,50,51,59,64Y69
However, there is evidence that knee injection thera-
peutic outcomes improve with accuracy, and this
may be more important with biologic agents such as
PRP.70,71 Previous studies suggest that the accuracy
of palpation-guided knee injections can be highly
variable (50%Y93%).72,73 Furthermore, it has been
shown that sonographically guided knee joint in-
jections are more accurate than palpation-guided
Month 2014
injections.74 Therefore, the use of image guidance
may enhance PRP injection efficacy for knee OA.
Injection Volume and Frequency
PRP injection volume and frequency are widely

varied among published knee OA studies, with no
clear standardization yet proposed. Injection volume
has ranged from as little as 3 ml to as high as
8 ml.37,44 Because the primary effects of PLT GFs
occur during approximately 8 days, most authors
have elected to performmultiple injections at weekly,
biweekly, every-3-wk, or monthly intervals to maxi-
mize effects.11,37,40,50,64 Nevertheless, positive effects
have been reported with a single injection, with one
clinical trial showing equivalent benefits in one vs.
two injections.38,59,65 The great variability of these
factors in the current literature makes it difficult to
derive specific recommendations.
Preinjection and Postinjection Protocol
Many specialists recommend avoiding nonste-
roidal anti-inflammatory drugs (NSAIDs) before
and after PRP treatment. NSAIDs have been shown
to have a negative effect on PLT function and, the-
oretically, may reduce PLT GF release.75 Previous
investigations have shown that NSAIDs slow the
healing rate of various tissues, including the bone,
tendon, and muscle.76 There are no data specifically
examining NSAID use with PRP. However, consid-
ering the pharmacokinetics of most NSAIDs and
the duration of the initial phase of tissue healing,
it seems reasonable to recommend avoidingNSAIDs at
least 5 days before and for 2 wks after PRP injection.77
It is unknown whether specific activity re-
strictions or rehabilitation after PRP knee joint in-
jection affect treatment outcomes. In studies to
date, postinjection activity recommendations have
ranged from no restrictions to temporary restric-

tion of activities with gradual return to full activi-
ty.37,51 Until further studies provide more guidance,
it is difficult to provide specific postinjection activ-
ity recommendations.
Disease Type and Severity
As with other knee OA treatments, the stage of
disease may be an important variable in determin-
ing appropriate patient selection for PRP treatment.
Studies to date have examined the effect of PRP on
knees affected by chondromalacia/early OA to ad-
vanced OA, with varying results (as will be discussed
later).25,38,67,68 Defining PRP efficacy in various
stages of knee OA is essential to guide specialists in
appropriate patient selection.
Patient-Specific Factors
Other patient factors may also be important to
recognize when considering PRP injection for knee
OA. Several clinical studies have suggested that
treatment efficacy may be decreased in older pa-
tients, although it is unclear whether this is simply
related to a tendency toward higher grade OA or
other yet unknown factors.25,44,50,51,59,69 Women have
had less robust results in some studies, perhaps re-
lated to biochemical or biomechanical differences.44,50
Logically, one may deduce that PLT-related comor-
bidities, such as thrombocytopenia, may negatively
affect PRP efficacy. The use of PRP in various knee
OA patient populations requires further study, and
potentially confounding patient factors should be
accounted for in future investigations.

Even though there are multiple studies show-
ing potential benefit of PRP injection for knee OA,
the numerous variables make study comparison
difficult. High-quality randomized controlled trials
that account for these factors are needed to opti-
mize PRP treatment of knee OA.
CLINICAL STUDIES OF PRP INJECTION
FOR KNEE OA
A PubMed search was performed using key
words Bplatelet-rich plasma or PRP or autologous
conditioned plasma or ACP and cartilage or chon-
drocyte or chondrogenesis or osteoarthritis or
osteoarthrosis or arthritis or growth.[ The search
included original manuscripts and review articles
from 1970 to September 2013. Case studies and
original research that specifically mentioned the
intraarticular use of PRP in knee OA were also in-
cluded. Studies investigating PRP exclusively for
osteochondral lesions were excluded. Sixteen pub-
lications were identified using this search and the
selection criteria. For simplicity, the summary
below is divided into case series, nonrandomized
cohort studies, and randomized controlled trials
(see Table 2).
Case Series
In 2010, Sampson et al.78 published a pro-
spective case series of 14 patients with unclassified
Bprimary and secondary OA[ of the knee. These
patients were treated with three 3-ml sonographically
guided injections of CaCl2- and thrombin-activated
PRP with an unspecified leukocyte and PLT concen-
tration, at 3-wk intervals. Patients were restricted

fromNSAID use 1 wk before treatment and 1mo after
treatment and were instructed to restrict the use
of the treated leg for 24 hrs after each injection.
Outcomes were measured at the 12-mo follow-up
with the Brittberg-Peterson Visual Analog Pain, Ac-
tivities and Expectations Scale, in addition to the
Knee Injury and Osteoarthritis Outcome Score
(KOOS). The authors also sonographically measured
the trochlear cartilage thickness before injection and
at 6 mos. Results indicated that PRP improved out-
comes in all measures with no significant sono-
graphic changes in cartilage thickness.
In addition, in 2010, Kon et al.44 published a
prospective case series on 91 patients (115 joints)
with Kellgren-Lawrence grades 1Y4 of knee OA.
Patients were treated with three 3-ml palpation-
guided injections of CaCl2-activated LR-PRP/lysate
with a PLT concentration of 6� BL, at 3-wk intervals.
After the procedure, patients were instructed to
restrict the use of the leg, ice, and avoid NSAIDs/
steroids for 24 hrs. Thereafter, mild activity (light
cycling/pool exercises) was allowed during the 42-day
injection cycle period with subsequent gradual return
to full activity. The International Knee Documentation
Committee (IKDC) subjective and objective question-
naire and EuroQol Visual Analog Scale (EQ-VAS) were
used to measure outcomes at 6 and 12 mos. Overall

patient outcomes improved at 6 mos, with subsequent
decline at 12 mos, although they remained improved
fromBL (P G 0.0005). Patients with higher OA severity
showed less improvement (cartilage lesion9Kellgren-
Lawrence 1Y3 9 Kellgren Lawrence 4). In addition,
older patients (965 yrs), women, and those with a
higher body mass index had less benefit, whereas
previous knee surgery did not seem to influence re-
sults. The most common adverse reaction reported
was postinjection pain and swelling that resolved
spontaneously at 2 wks.
In 2011, the same authors reported on this
same patient population at 24 mos, with only one
patient lost to follow-up (114 joints).50 All evaluated
parameters worsened by 24 mos, although re-
mained improved from BL (P = 0.0014). Median
duration of beneficial effect was 9 mos. Younger
patients, men, and patients with less severe OA (by
Kellgren-Lawrence grading as above) had better
results and a longer duration of benefit.
Wang-Saegusa et al.64 in 2011 reported the
results of their prospective case series on 261 pa-
tients (359 joints) with Outerbridge grades 1Y4 of
knee OA. Patients in this study received three 5-ml
palpation-guided injections of CaCl2-activated LP-
PRP with an unspecified PLT concentration, at 2-wk
intervals. There were no postinjection physical ac-
tivity or NSAID restrictions mentioned. Outcomes
were measured with the VAS for Pain, Short Form
(36) Health Survey (SF), Western Ontario and
McMaster Universities Arthritis Index (WOMAC), and
Lequesne index at 6-mo follow-up. Similar to previ-
ous smaller studies, patients displayed statistically

significant improvements in all pain and functional
outcomes.
In 2013, Halpern et al.65 published a case series
of 17 patients (18 joints) with Kellgren grades 1Y2 of
knee OA. Of the included joints, 15 had preinjection
and postinjection magnetic resonance imaging. All
knees were injected with a single 6-ml palpation-
guided injection of LP-PRP. There was nomention of
PRP preactivation or specific PLT concentrations.
Postinjection physical activity and NSAID restriction
were also not specified. Outcomes were measured
with VAS (pain, function, and activities of daily living)
and WOMAC scores at 12 mos. Pain and function
improved with statistical significance in all patients,
with nomagnetic resonance imaging changes in 73%
of the patients at 1 yr.
Nonrandomized Cohort Studies
In 2008, Sánchez et al.37 published the first
study examining PRP in knee OA, a retrospective
cohort study of 60 patients (two groups) with uni-
lateral Ahlbäck grades 1Y4 disease. The first group
of 30 patients was treated with three 6- to 8-ml
palpation-guided injections of CaCl2-activated LP-
PRP with a PLT concentration of È2� BL, at 1-wk
intervals. The second group of 30 patients was
treated with three 2-ml injections of high-
molecular-weight hyaluronic acid (HWHA), also at
1-wk intervals. NSAID or postprocedure activity
restrictions were not specified. The WOMAC was
used to assess clinical outcomes in pain, stiffness,
and function. Treatment success rates (40% of de-
crease in WOMAC pain score) were also measured.
Both groups showed statistically significant benefits

in pain and function. However, the PRP group had
a higher treatment success rate with greater pain
and functional improvements at 5-wk follow-up,
all with statistical significance. Although encourag-
ing in demonstrating the feasibility and short-term
safety of intraarticular PRP injections, this investi-
gation was limited by its very short-term follow-up.
In 2011, Kon et al.51 published a multicenter
three-arm prospective cohort study of 150 patients
with unilateral Kellgren grades 1Y4 OA. In this
study, the clinical efficacy of PRP was compared
with the efficacy of low-molecular-weight HA
(LWHA) and HWHA. Patients in the PRP arm (50
joints) received three 5-ml palpation-guided in-
jections of CaCl2-activated LR-PRP/lysate with PLT
Month 2014
(C
on
ti
nu
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on
ne
xt
pa

ge
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TA
B
LE
2
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lin
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…
RESEARCH ARTICLE Open Access
Effects and safety of the combination of
platelet-rich plasma (PRP) and hyaluronic
acid (HA) in the treatment of knee
osteoarthritis: a systematic review and
meta-analysis
Jinlong Zhao1,3† , Hetao Huang1,3† , Guihong Liang1,3† ,
Ling-feng Zeng2,3 , Weiyi Yang2,3 and Jun Liu2,3*
Abstract
Background: Studies have shown that the combined application
of hyaluronic acid (HA) and platelet-rich plasma
(PRP) can repair degenerated cartilage and delay the
progression of knee osteoarthritis (KOA). The purpose of this
study was to explore the efficacy and safety of the intra-
articular injection of PRP combined with HA compared
with the intra-articular injection of PRP or HA alone in the
treatment of KOA.
Methods: The PubMed, Cochrane Library, EMBASE and China
National Knowledge Infrastructure (CNKI) databases were
searched from inception to December 2019. Randomized
controlled trials and cohort studies of PRP combined with HA
for
KOA were included. Two orthopaedic surgeons conducted the
literature retrieval and extracted the data. Outcome

indicators included the Western Ontario and McMaster
Universities Arthritis Index (WOMAC), the Lequesne Index, the
visual
analogue scale (VAS) for pain, and adverse events (AEs).
Review Manager 5.3 was used to calculate the relative risk (RR)
or
standardized mean difference (SMD) of the pooled data. STATA
14.0 was used for quantitative publication bias evaluation.
(Continued on next page)
© The Author(s). 2020 Open Access This article is licensed
under a Creative Commons Attribution 4.0 International
License,
which permits use, sharing, adaptation, distribution and
reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in
this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article's Creative
Commons
licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy
of this licence, visit
http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to
the
data made available in this article, unless otherwise stated in a
credit line to the data.
* Correspondence: [email protected]
†Jinlong Zhao, Hetao Huang and Guihong Liang contributed

equally to this
work.
2The Second Affiliated Hospital, Guangzhou University of
Chinese Medicine
(Guangdong Province Hospital of Traditional Chinese
Medicine), Guangzhou
510120, China
3Guangdong Academy of Traditional Chinese Medicine,
Research Team on
Bone and Joint Degeneration and Injury, Guangzhou 510120,
China
Full list of author information is available at the end of the
article
Zhao et al. BMC Musculoskeletal Disorders (2020)
21:224
https://doi.org/10.1186/s12891-020-03262-w
http://crossmark.crossref.org/dialog/?doi=10.1186/s12891-020-
03262-w&domain=pdf
https://orcid.org/0000-0001-7079-1336
https://orcid.org/0000-0002-6197-1375
https://orcid.org/0000-0002-7599-2628
https://orcid.org/0000-0003-1311-8641
https://orcid.org/0000-0001-8657-2269
https://orcid.org/0000-0002-1943-3880
http://creativecommons.org/licenses/by/4.0/
http://creativecommons.org/publicdomain/zero/1.0/
mailto:[email protected]
(Continued from previous page)
Results: Seven studies (5 randomized controlled trials, 2 cohort
studies) with a total of 941 patients were included. In
the VAS comparison after 6 months of follow-up, PRP

combined with HA was more likely to reduce knee pain than
PRP
alone (SMD: − 0.31; 95% confidence interval (CI): − 0.55 to −
0.06; P = 0.01 < 0.05). PRP combined with HA for KOA
achieved better improvements in the WOMAC Function Score
(SMD: -0.32; 95% CI: − 0.54 to − 0.10; P < 0.05) and
WOMAC Total Score (SMD: -0.42; 95% CI: − 0.67 to − 0.17; P
< 0.05) at the 12-month follow-up than did the application
of PRP alone. In a comparison of Lequesne Index scores at the
6-month follow-up, PRP combined with HA improved
knee pain scores more than PRP alone (SMD: -0.42; 95% CI: −
0.67 to − 0.17; P < 0.05). In terms of AEs, PRP combined
with HA was not significantly different from PRP or HA alone
(P > 0.05).
Conclusions: Compared with intra-articular injection of PRP
alone, that of PRP combined with HA can improve the
WOMAC Function Scores, WOMAC Total Score, 6-month
follow-up VAS ratings, and Lequesne Index scores. However,
in terms of the incidence of AEs, PRP combined with HA is not
significantly different from PRP or HA alone.
Keywords: Platelet-rich plasma, Hyaluronic acid, Knee
osteoarthritis, Meta-analysis
Background
Knee osteoarthritis (KOA) is a common knee degenera-
tive disease characterized by cartilage degeneration, car-
tilage exfoliation, and subchondral bone hyperplasia,
leading to knee pain, joint instability and functional limi-
tations [1]. KOA severely affects patients’ quality of life
and is a major public health issue [2]. An epidemio-
logical survey published in Proceedings of the National
Academy of Sciences (PNAS) showed that the incidence
of KOA in the U.S. population has doubled since the
mid-twentieth century [3]. KOA has become a high-

incidence human disease and has caused a great negative
impact on people’s lives and work.
The Osteoarthritis Society International (OARSI) recom-
mends conservative treatment rather than surgery as the
first-line management solution for KOA, which emphasizes
the importance of conservative treatment in the treatment of
KOA [4]. The American College of Rheumatology (ACR)
has proposed a classification in which conservative treatment
includes drug treatment and non-drug treatment [5]. Non-
drug treatment includes general exercise and muscle exer-
cise, but non-drug methods often depend heavily on patient
compliance and are difficult to control [5]. The main drug
therapies include analgesics, non-steroidal anti-inflammatory
drugs and corticosteroid injections [6]. Although the above
drug therapies are effective to a certain degree, there are also
major side effects [6, 7]. In recent years, there have been an
increasing number of studies on the application of intra-
articular injection of platelet-rich plasma (PRP) or hyaluronic
acid (HA) in the treatment of KOA. Many systematic re-
views suggest that intra-articular injection of PRP, compared
to HA, can alleviate pain symptoms and improve knee func-
tion in patients with KOA [6, 8, 9]. However, a double-blind
randomized controlled trial with a 5-year follow-up showed
that the combination of HA and PRP improved pain and
function in patients with a history of chronic symptomatic
knee degenerative changes and osteoarthritis [10]. An RCT
showed that PRP is an effective treatment for mild to
moderate KOA and that the combined use of HA and PRP
is better than the use of HA (1 year) and PRP (3months)
alone [11]. The RCT also revealed that PRP does not pro-
vide better overall clinical improvement than HA in terms
of symptom-function improvement at different follow-up
points or in terms of duration of effect [10]. In recent
years, an increasing number of studies have focused on

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