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CLINICAL TRIAL REPORT
Platelet-Rich Plasma-Derived Growth Factor vs
Hyaluronic Acid Injection in the Individuals with
Knee Osteoarthritis: A One Year Randomized
Clinical Trial
This article was published in the following Dove Press journal:
Journal of Pain Research
Seyed Ahmad Raeissadat
1
Azadeh Gharooee Ahangar
2
Seyed Mansoor Rayegani
1
Mohammadreza Minator Sajjadi
3
Adel Ebrahimpour
3
Pegah Yavari
1
1
Physical Medicine and Rehabilitation
Research Center, Clinical Research
Development Center of Shahid Modarres
Hospital, Shahid Beheshti University of
Medical Sciences, Tehran, Iran;
2
Department of Orthopedic Surgery,
Zanjan University of Medical Sciences,
Zanjan, Iran;
3
Taleghani Hospital, Shahid
Beheshti University of Medical Sciences,
Tehran, Iran
Objective: In this study, we aimed at performing a comparison between intra-articular
injections of PRP-derived growth factor (PGRF) and hyaluronic acid regarding their effect
on pain and patient’s function in knee osteoarthritis, as well as their safety profiles.
Methods: During our single-masked randomized clinical trial, the candidates with symptomatic
knee osteoarthritis received two intra-articularinjections of PRGF with 3 weeks apart or received
three weekly injections of HA. The mean improvements from before treatment until the second,
sixth, and twelfth months post-intervention in scores obtained by visual analog scale (VAS),
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lequesne
index were our primary outcomes.
Results: A total of 102 candidates were finally included in the study. Patients’mean age was 57.08
±7.3 years old in the PRGF group compared to the mean age of 58.63±7.09 years old in HA patients.
In the PRGF group, total WOMAC index decreased from 41.96±11.71 to 27.10±12.3 (P = 0.02),
and from 39.71±10.4 to 32.41±11.8 in the HA group after 12 months (P > 0.05). Regarding the
Lequesne index, pain, ADL, and global scores significantly decreased after 12 months in the PRGF
group compared to the HA group (P<0.001). There was also a meaningful higher rate of satisfaction
in the PRGF group compared to the HA group after 12 months of treatment (P<0.001).
Conclusion: Besides significantly higher satisfaction belonging to the PRGF group, there
was a statistically significant improvement in VAS score and global, pain, and ADL score of
Lequesne by passing 12 months from injection in PRGF compared to HA.
Keywords: knee, osteoarthritis, PRP, PRP-derived growth factor, hyaluronic acid, intra-
articular injections
Introduction
Osteoarthritis (OA) is a joint disease with the highest prevalence worldwide.
Accordingly, its characteristic signs are as follows: increasing the loss of joint
cartilage, synovial membrane changes, and reduction in the synovial fluid
viscosity.
1
In this regard, at first, erosion of articular cartilage and exposure of the
bone under the cartilage occur in OA, resulting in the inflammation of the surround-
ing tissues. This complication may involve any joint, with cartilage destruction
being the trademark sign of osteoarthritis.
2–4
Since, at the moment, osteoarthritis lacks a definite cure, symptomatic relief is
the foundation of treatment; however, reducing the pain and disability and
Correspondence: Pegah Yavari
Physical Medicine and Rehabilitation
Research Center, Clinical Research
Development Center of Shahid Modarres
Hospital, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
Tel + 98 912 299 7782
Email p3gi69@yahoo.com
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maintaining or improving joint mobility is the mainstay
management. Also, non-surgical modalities such as exer-
cise and weight reduction, are preferred due to having less
satisfactory symptomatic and functional results of
surgery.
6–8
On the other hand, patient compliance with
non-surgical approaches is weak, while some medications
such as standard painkillers and NSAIDs may have the
risk of adverse effects.
5,10,11
Recent studies have worked on new non-surgical
approaches including Intra-Articular Injection (IAI) of hya-
luronic acid (HA), ozone therapy, prolotherapy, intra-articular
botulinum toxin administration, and platelet-rich plasma
(PRP), which are considered as the favored candidates
among the existing management options for knee OA.
12–16
HA is a chief viscoelastic constituent of the synovial fluid
present inside the joints with lubricant and cushioning proper-
ties. In an OA-affected patient, a reduction occurs in the con-
centration and molecular weight of HA, which as a result,
affects its properties. In clinical practice, it was shown that,
infiltration of HA in the joint can temporarily restore the joint’s
normal function, giving the patient symptom relief. Also, the
effectiveness of HA in knee OA treatment has been shown in
a number of clinical trials.
17–20
Moreover, HA has a longer-
lasting effect compared to corticosteroid infiltrations.
21,22
Considering the direct costs and the costs associated with the
potential side effects, the cost-effectiveness of HA compared to
oral NSAIDs, physical therapy, and assistive devices has been
reported in the literature. Despite the lack of certain evidence
on the recent guidelines, intra-articular HA has been used for
several years, which is considered as the standard treatment in
knee OA.
19,20
PRP is a blood component with non-transfusion usage,
utilized to treat many pathologies as a topical agent, as injec-
tions for tendons or ligament injury, IA injections in osteoar-
thritis or very recently in carpal tunnel syndrome.
24
PRP is
collected from the blood of each patient and is used for that
patient; so, it is considered as a safe practice.
25,26
PRP treat-
ment efficacy have been reported in several studies, particu-
larly in the first years of treatment.
27–31
It is also possible to
perform PRP injections in the office. Accordingly, its thera-
peutic benefits are thought to be resulted from the increased
concentration of the platelet-derived growth factors in the
alpha granules of the platelets injected into the knee.
32–34
The
roles of these growth factors are affecting the chondrocytes,
promoting the synthesis of the cartilage matrix, increasing the
growth and migration of cells, and facilitating protein tran-
scription. The theory behind the use of PRGF is the supra-
physiological amounts of platelet-derived factors that are
directly delivered at the site of the damaged cartilage such as
OA, and can trigger the natural healing process and tissue
regeneration as well as facilitation of the anti-inflammatory
response.
Of many biologic treatments employed for modifying
symptoms in OA treatment, plasma rich in growth factors
(PRGF) articular injection has proven its safety and efficacy
as an autologous treatment method.
36–38
TheroleofPRGF”
preparation rich the followings in growth factors: a low-
concentrate PRP with no leukocytes on OA synoviocytes
with or without exposition to IL-1ß, to mimic the overproduc-
tion of pro-inflammatory cytokines in the joint environment
during OA progression”, which was investigated by Anitua
et al Accordingly,their results showed significant enhancement
of HA secretion relative to PRP, and irrespective of IL-1b. It
also modified angiogenesis to a more balanced status.
Moreover, this concentrated platelet suspension in plasma
leadstotheformationofaninsitumatrixoffibrin and also
facilitates the delivery of growth factors, cytokines, and mor-
phogens
40
(IGF-1, TGFB1, HGF, PDGF, VEGF, NGF, BDNF,
CTGF, BMPs, vitronectin, fibronectin, SDF-1, and PF4 among
others), all of which proven chondroprotective, anabolic, anti-
inflammatory, and immunomodulatory properties.
41–45
This
product showed encouraging results in knee OA, while it
indicates lower complications such as pain and swelling after
injection. In contrast to PRP, which has been compared with
placebo or HA in many studies in the literature showing con-
flicting results,
38,46-48
the evidence is scarce when it comes to
investigate the use of PGRF articular injection in improving
long term outcome, compared to HA in the patients with knee
OA.
26,49
Our previous study demonstrated that, the pain reduction
and functional improvement effects of PGRF and HA are very
close in those patients suffering from mild to moderate knee
OA. In this regard, both products retained their positive effect
up to 6 months, while showing no meaningful difference. The
goal of the present study was to compare the 12-month clinical
efficacy and safety of intra-articular injections of PRP-derived
growth factor (PRGF) with HA on the patients with knee OA
using WOMAC, LEQUESNE, and VAS scores used as the
outcome measures.
Materials and Methods
The present study conducted a long-term follow-up on the
existing clinical trials published in our department. Our
randomized clinical trial (RCT) was performed in
Moddares Medical Center of Tehran, Iran, from
July 2016 to September 2018. The institutional review
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board approved this RCT design and methodology, which
were then registered in the Iranian Registry of Clinical
Trials (www.irct.ir), regulatory representative of the
World Health Organization for Iranian clinical trials, with
registration code of IRCT2016071513442N11.
The main purpose of this comparative RCT was asses-
sing the efficacy of these two therapeutic groups treated by
intraarticular injection of plasma rich in growth factor
(PRGF) and hyaluronic acid (HA) in the patients with
knee osteoarthritis (OA) at the 2nd, 6th, and 12th months
after injection.
Patient Selection and
Randomization
The signed written informed consent was obtained from all
research units prior to participation in this RCT. A knee
x-ray was prepared in anteroposterior weight-bearing, and
lateral views to diagnosing and grading OA. A specialist in
physical medicine and rehabilitation explained the study
design, objectives, advantages, and side effects for those
patients who met the inclusion criteria. Subsequently, the
selected subjects were assigned into two groups (Group I:
received IAIs with PRGFs and Group II: received IAIs
with HA) using the permuted block randomization
method. An assistant who was a resident in physical med-
icine and rehabilitation, and was also unaware of the group
allocation, performed the recruitment and randomization.
The inclusion criteria were the age of 40–70 years old,
suffering from knee pain in the past six months, history of
complaints for at least one month, the need for painkillers,
and knee osteoarthritis confirmed by radiography
(Kellgren-Lawrence classification grade 2–3). In addition,
the exclusion criteria were the presence of systemic dis-
orders (ie, diabetes mellitus, immunodeficiency, and col-
lagen vascular diseases), the history of malignancy, the
history of autoimmune diseases or platelet disorders,
body mass index of over 33 kg/m2, and the use of non-
steroidal anti-inflammatory drugs (NSAIDs) within the
past two days or aspirin within the seven days before the
injection, the use of anticoagulant or antiplatelet medica-
tions within ten days before the injection, the history of
systemic steroids in two weeks before the injection, the
presence of IAIs within the past three months before the
injection, the hemoglobin level of less than 12 g/dl or
platelet count of less than 150 000/μl36, the history of
a recently occurred severe knee trauma, knee septic arthri-
tis, the active ulcer or septic arthritis of knee, genu varum
or valgum of over 20°, allergy to proteins of egg and
chicken or HA, and the use of ginger or turmeric within
a week before the injection.
Product Preparation
In the present study, the Group I separately received two
and three weeks of IAIs with platelet-rich plasma (PRP)-
derived growth factor (PRGF), which were prepared in
terms of the following protocol. At first, the PRP was
produced from the participants who were referred to the
laboratory of the hospital using Rooyagen Kit (Arya
MabnaTashkhis Corporation, RN: 312,569) with the
behind principle of a dual-spin system aseptically. To fulfil
this, 35 CC of blood samples were taken from the patients
to obtain PRP having a concentration of 4 to 6 times more
than the mean normal values, which were then added by
5 mL of citric acid dextrose solution A for anticoagulation.
Complete blood count (CBC) was also measured using
1 mL of the collected samples. Afterward, the blood sam-
ples were centrifuged for 15 min at 1600 rpm, resulting in
three phases of red blood cells (lower), white blood cells
(middle), and plasma (upper). The two uppermost layers
were centrifuged again for 7 minutes at 3500 rpm. The
final resulting product contained 8 mL of plasma with 4.6
± 0.7 times more than the platelet concentration.
Next, 1.5 mL of platelet-activating factor (Rooyagen)
containing epinephrine and calcium chloride (25mmol/l)
was poured, stirred, and then placed in warm water for
20–30 min at 40±1°C to release the platelet factors, which
occurs due to platelet activation, in which fibrin interacts
with platelets through glycoprotein IIa/IIIb surface pro-
teins, hereby producing growth factors by platelets.
In this step, two phases were formed in a plasma pre-
paration named as the supernatant liquid phase (PRGF)
and the solid phase (platelet clumps+fibrin network). The
third centrifugation stage was performed for 4 minutes at
4000 rpm to separate platelets and fibrin stick attached to
the bottom of the tubes. The remaining fluid (5 mL) was
injected within 20 minutes of its preparation, and no local
anesthetics were used before plasma product injection.
The level of various growth factors present in the final
product PRGF was evaluated in 10 volunteers of the
PRGF group, which resulted in vascular endothelial
growth factor (312±23.2ng/mL), PDGF (279±52.1ng/
mL), IGF (1.3±0.7ng/mL), TGF-β1 (2.0±0.1ng/mL), and
TGF-β2 (1.1±0.3ng/mL). Also, no platelet or WBCs was
found in our product, and the hepatocyte growth factor
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level was measured as 321pg/mL, using an enzyme-linked
immunosorbent assay method.
Interventions
After disinfection, the lateral mid-patellar injection of
PRGF was performed using G21 needles with the knee
extended. Moreover, an anteromedial method with flexed
knee was applied for a patient, because of inadequate
space. Active knee flexion and extension were prescribed
after a 20-min rest for the injected fluid dispersion inside
the entire synovial space. After three weeks, the same
injection settings were repeated for the second time, and
the number of injections was determined in terms of the
experiences of the authors due to having no consensus in
this regard. The group II underwent three injections of HA
weekly (Hyalgan
®
, FidiaFarmaceutici S.p.A., Abano
Terme, Italy). In case of feeling any pain, a single dose
of acetaminophen (500 mg, oral) was given to the patients
two hours after the injection.
The content of each prefilled syringe was the active ingre-
dient sodium hyaluronate (20 mg) in the liquid (2 mL) with
a molecular weight of 500 to 730 kDa. The injection of hyalgan
syringes was aseptically performed via G21 needles based on
the same above-mentioned protocol. After injections, the sub-
jects were requested for their knee flexion and extension for
several times. The same injection processes were performed
for the second and third injections with a week of interval.
A similarly skilled specialist in physical medicine and rehabi-
litation, who was not blinded to group allocation, performed
theIAIsinthesetwogroups.
Follow-Up After Interventions
The discharge of the patients was after a rest time of 10–15
min. Besides, only mild physical activities and limited
weight-bearing over the involved lower limb were
instructed for the patients.
The therapeutic exercise was administered to the patients in
both groups. One week after the first injection, the patients
were asked to report the exercise process. Moreover, one
month after the first injection, the patients were asked again
via phone call. In follow-ups, the patients were also asked
about their exercise to make sure that the patients were reg-
ularly performing the exercise.
Accordingly, they were also recommended to use an
ice pack daily for 10 minutes every 8 hours, through the
first two days. Moreover, up to four 500-mg acetamino-
phen tablets were proscribed for the possible mild to
moderate pain, or codeine/acetaminophen for the persisted
pain. Other analgesics were also prohibited up to 5 days
after injection. This research authors recommended routine
knee-oriented exercise therapy for both groups.
Another blinded resident assistant followed up all the
subjects at the clinic after the 2nd, 6th, and 12th months of
injections. The intensity of pain, joint stiffness, and pro-
blems with the injection site were monitored, and the
number of painkillers consumed was then checked con-
tinuously. A 24-h phone line was considered in case of any
emergent condition. The reason for the absence of each
patient in timely visits was followed up for any possible
exclusion from the study.
Outcome Measures
At the baseline, we collected demographic profiles (sex, age,
body mass index BMI), clinical characteristics, and degree of
osteoarthritis measured by with Kellgren-Lawrence score,
laterality, and side effects. Additional measures were also
performed at baseline and at the 2nd, 6th, and 12th months of
follow-up. Primary outcomes in our study were considered as
a reduction of pain and an improvement of function by asses-
sing the decreased global score of the WOMAC Index
(Western Ontario and McMaster University Osteoarthritis
Index)
51
along with the subscales of pain, stiffness, and
physical function, and the decreased global score of
LEQUESNE Index
52
and the relevant subscales of pain,
maximum walking distance (MWD) and activities of daily
living (ADL), as well as Visual Analogue Scale (VAS) at the
baseline and at the 2nd, 6th, and 12th months (48 weeks) after
the injection.
The secondary outcome was considered as the patients’
satisfaction after 12 months and the injection-related
complications.
Safety Assessments
We analyzed and then documented the grade of severity,
received treatment, and complications for each visit. The
patient’s diaries consisted of a daily usage of rescue
medication.
Sample Size Calculation
The sample size was 50 in each group by considering the
results from the earlier study
50
regarding a significant
mean difference in the decreased scores of WOMAC and
LEQUESNE, the equation for calculating the sample size
to compare two means, and the test power of 80% at the
significance level of 0.5. The difference between the effi-
cacies of these two therapeutic methods was described as
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effect size (raw mean difference [RMD]) and then ana-
lyzed using Mann–Whitney U-test.
Statistical Analysis
A medical statistics expert who was blinded to the group
allocation inserted the attained data from pre/post-treatment
to the computer and then analyzed them by SPSS v.16 soft-
ware using Shapiro–Wilk or Kolmogorov–Smirnov for the
evaluation of data normality, independent samples t-test for
comparing the mean scores between these two groups, and
the repeated measures analysis of variance (ANOVA) for
assessing the intra/inter-group changes.
Results
Patient Characteristics
From 211 candidates with knee osteoarthritis who were
eligible to participate in our study, 92 patients were
excluded, and 119 candidates were then included in this
study and had IAIs (PRGF=60, HA=59). During the 12
months of this study, 7 patients in HA group and 10
patients in PRGF group were excluded from the study
(because of missing follow up, total knee arthroplasty,
the increased knee pain, IAI ozone therapy, and PT) and
50 patients in PRGF and 52 in Hyalgan groups completed
the study protocol (Figure 1). The candidates’mean age
was 57.81 ± 7.2 years old (43–70), 71.6% of the patients
were female, and 21 (73.9%) patients were obese or over-
weight. The initial characteristics of this study subjects are
shown in Table 1. As can be observed, the subjects were
statistically matched between the two groups.
Outcomes
The VAS for pain, WOMAC, and Lequesne instrument
mean scores acquired by the subjects at baseline and at the
2nd, 6th, and 12th months after injection are shown in
Tables 2 and 3.
Based on ANOVA for the repeated measures, the
decreased pattern observed in WOMAC and VAS was
statistically significant within each group during the
study time (F=108.8, P<0.001).
During 12-month follow-up, VAS score was signifi-
cantly higher in the HA group (PRGF vs HA, 4.59: 6.18)
(F = 0.02, P < 0.0001). Also, HA group had significantly
higher scores in sub-score of function in the WOMAC
index (PRGF vs HA, 19.82: 24.43) (F = 0.2, P = 0.009).
The WOMAC global score was also significantly higher in
the HA group compared to the PRGF group (27.1: 34.
PRGF vs HA) (F = 0.1, P = 0.02).
The %change from baseline was calculated with the
following formula:
([Baseline score –12th month score/Baseline
score] *100).
According to Table 3, there was no statistically signifi-
cant difference between these two groups at baseline and
after two months of injection in each one of the scores (p>
0.05). By passing 6 months from injection, a significant
difference was observed in the subscale of Lequesne activ-
ities of daily life (ADL), which shows that HA injection
group had a higher score (F = 3.7, P = 0.009).
Also, after 12 months, significant differences were
observed in Lequesne global, pain, and ADL sub-scales
scores between these two groups. HA group had a higher
score in pain (PRGF vs HA, 3.71: 4.58), ADL (PRGF vs
HA, 4.78: 5.36) and the global score (PRGF vs HA, 10.20:
11.67), (P <0.05). Figures 2–4show the changes of total
WOMAC, Lequesne, and VAS scores during 12 months of
study in both groups.
The success rates of both interventions were defined as
any reduction of approximately 30% or higher from base-
line scores, when assessed for the third time by passing 12
months from the intervention. According to this definition,
success rates for each scale were as follows (PRGF vs
Hyalgan): WOMAC total 72.5% vs 22.4% (P < 0.001),
WOMAC pain 68.6% vs 74.5% (P =.661), WOMAC stiff-
ness 74.5% vs 19.6% (P < 0.001), and WOMAC function
74.5% vs 19.6% (P < 0.001). By considering P values,
there were significantly higher success rates in total, stiff-
ness, and function scores of WOMAC in the PRGF group.
In this regard, Table 2 shows WOMAC subscale scores
before, and after the 2nd, 6th, and 12th months of inter-
vention in both groups.
Based on the Lequesne scale scores, the rates of suc-
cess regarding various subscales (PRGF vs HA) were as
follows: 21.6% vs 7.8% for total (P=.091), 45.1% vs
19.6% for pain (P=.011), 92.2% vs 96.1% (P=.408) for
walk, and 21.6% vs 3.9% for the activities of daily life
(P=.015). At the end of the follow-up, the mean satisfac-
tion scores within a range of 0 to 5 were 2.43 ± 1.25 and
1.33 ± 1.07 in PRGF and Hyalgan group, respectively
(P<.001). In PRGF study groups, 54.9% and in the HA
group, and 15.7% of the subjects had a good or very good
satisfaction regarding the procedure they had undergone.
The rate of satisfaction is presented in Table 4.
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Minor complications because of injection occurred in
10 (19.6%) and 3 (5.9%) subjects in PRGF and Hyalgan
groups, respectively (P=.076). In this regard, swelling
(one in PRGF vs none in Hyalgan) or stiffness and heavi-
ness of injection site (other cases) were the mentioned
ones.
Discussion
This was a single-blinded randomized controlled study
comparing intra-articular injections of a newly developed
PRGF compared to HA. Also, the results of this study
show that, in the HA group, WOMAC, Lequesne and
VAS scores significantly reduced after two months but
then increased in 6 and 12 months post-injection; however,
they were significantly lower in comparison to baseline
scores. In PRGF groups, WOMAC and Lequesne scores
significant reduction continued up to the sixth month and
then increased up to 12th month after injection that were
significantly lower in comparison to baseline scores.
Beside significantly higher satisfaction in the PRGF
group, there were statistically significant improvements
after 12 months’post-injection in VAS score and global,
pain, and ADL score of Lequesne test in PRGF compared
to HA.
Previous studies performed in vitro and in vivo have
also found that, PRP and its consisting growth factors
including HGF, IGF-1, and PDGF, have a suppressive
effect on the activation of macrophages, fibroblasts, and
chondrocytes by inhibiting the NFkB signaling
pathway;
40–43
thus controlling the catabolic loop. As
a result, the inflammatory responses of the synovial and
articular cartilage will be blunted when exposed to pro-
inflammatory cytokines, abnormal mechanical stress, and
DAMPs, which are the characteristics of the OA
conditions.
4
Also, the considerable concentration of endo-
genous cannabinoids within PRP
53
might play the role of
ligands for cannabinoid receptor 1 (CB1) and 2 (CB2) of
chondrocyte and synovium cells of the OA patients
54,55
thereby assisting pain reduction through the endogenous
cannabinoid system.
53,54
The positive results of HA may be related to the
improved impermanent lubrication due to the viscoelasti-
city and the improvement of the intra-articular environ-
ment by repairing the space between the synovial
membrane and the articular surface. Moreover, the growth
factors secreted from active platelets play an essential role
in stimulating proliferation and differentiation of chondro-
cytes, regulating collagenase secretion, and regeneration of
cartilage.
An abundance of clinical studies has also shown that,
HA relieves joint pain as well as improving the joint
function.
58–60
Although several studies have been conducted on com-
paring the effects of PRP and HA on knee OA, limited
Allocated to MLC901
group
N=48
59 HA
211 Eligible Patients
119 Randomized
Diabetes Mellitus (n=47)
Rheumatoid Arthritis(n=6)
History of trauma(n=8)
History of surgery(n=4)
Cancer(n=3)
IAI in past 3 months(n=9)
Anti-coagulant therapy(n=4)
More than 20 degree of varum or valgum
in knees(n=11)
Excluded(n=92)
60 PRGF
Loss of follow up(n=3)
Total Knee
arthroplasty(n=1)
IAI ozon therapy(n=2)
Physical therapy(n=4)
Total Knee arthroplasty(n=2)
IAI ozon therapy(n=1)
Physical therapy(n=2)
Increased Knee pain(n=2)
50(83.3%)
Completed the
study and 12
months follow up
52(88.1%)
Completed the
study and 12
months follow up
Figure 1 Enrollment and allocation diagram. IAI, intra-articular injection; HA, hyaluronic acid; PRGF, plasma rich in growth factor.
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clinical trials have been conducted on examining the long
term outcomes of PRGF and HA in OA. Moreover, our
previous study showed that, our newly developed PRGF,
as well as HA, are both effective options on decreasing
pain and improvement of function in the patients with
symptomatic mild to moderate knee osteoarthritis by pas-
sing six months from injection.
This meaningful clinical improvement assessed by
both LEQUESNE and WOMAC scores in the patients
with knee OA treated with intra-articular injections of
PRGF, was observed in this study, which is in line with
the previously reported results. The Duymus et al’s
study showed that, in the 6th month, while the clinical
efficacies of PRP and HA were similar and continued,
and at the end of the 12th month, PRP was determined
to be both statistically and clinically superior to HA (p
< 0.001). In agreement with that, the Dai et al’s study
indicated that, compared with HA and saline, intra-
articular PRP injection may be more beneficial on
pain relief and functional improvement in the patients
with symptomatic knee OA at 12 months post-
injection.
62
In a retrospective cohort study performed by Sánchez
et al, success rates by the 5th week for the pain subscale
reached 33.4% for the PRGF group and 10% for the
hyaluronan group.
26
In another study, Vaquerizo et al
reported that, PRGF-Endoret is safe and significantly
superior to HA in primary and secondary efficacy analysis
both at the 24th and 48th weeks that provided a significant
clinical improvement, reduced the patients’pain, and
improved joint stiffness and physical function compared
to basal levels in the patients with knee OA.
38
Wang-
Table 1 Initial Characteristics of the Study Subjects
PRGF HA P-value Total
Age (mean±SD) 57.08±7.3 58.63±7.09 0.4 57.85±7.2
Gender (M/F) 14/36 15/37 0.8 29:73
BMI (kg/m
2
) 27.92±2.7 28.65±3.02 0.1 28.24±2.8
Duration of pain,y 6.61±4.7 5.64±3.3 0.5 6.12±4.1
Right:left 20:31 26:25 0.2 46:56
Kell gr en -Lawrence
classification grade
(II/III)
20/31 21/30 0.8 41:61
History of previous
physiotherapy
74.5% 56.9% 0.07 65.7%
History of
previous injection
(HA or CS)
52.9% 31.4% 0.02 42.2%
Injection-induced
pain score
3.65±2.4 1.86±1.2 0.001 2.75±2.1
Abbreviations: BMI, body mass index; HA, hyaluronic acid; PRGF, plasma rich in
growth factor; CS, corticosteroid.
Table 2 WOMAC and VAS Mean Scores at Baseline, and at the 2nd, 6th, and 12th Months After Injection
WOMAC Index
Pain Stiffness Function Total VAS
PRGF HA PRGF HA PRGF HA PRGF HA PRGF HA
Baseline 8.25±2.7 8.14
±2.6
2.86
±1.8
2.57
±.1.4
30.75±8.5 29±8.1 41.96
±11.71
39.71
±10.4
7.8±1.5 7.8±1.1
At 2nd m 4.98±2.6 5.31
±2.3
1.53
±1.4
1.2±1.1 19.75±8.2 20.78
±6.6
26.25
±11.17
27.37
±9.09
4.2
±2.01
4.4±1.6
At 6th m 5.22
±3.05
5.9±2.3 1.43
±1.5
1.2±1.2 18.22±9.9 21.12
±6.6
24.86±14 28.35±9.4 4.3±2.3 4.7±1.9
At 12th m 5.47±2.6 6.3±2.6 1.8
±1.34
1.6±1.2 19.82±8.9 24.43
±8.4
b
27.10
±12.3
32.41
±11.8
4.5±1.7 6.1±1.8
Raw mean difference
(SE)
−2.8±1.8 −2.6
±0.4
−1±1.2 −0.9
±0.01
−10.93
±8.3
−4.6±1.2 −14.08
±11.8
−5.3±2.9 −3.3
±1.9
−1.7
±1.3
P-value Within groups <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
P-value Between
groups
0.339 0.856
a
0.009
b
0.02
c
0.0001
Notes:
a
PRGF vs HA Function score at the 12th month.
b
PRGF vs HA, Total score at the 12th month.
c
PRGF vs HA, VAS score at the 12th month.
Abbreviations: WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; HA, hyaluronic acid; PRGF, plasma rich in growth factor ; VAS, visual analog
scale.
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Saegusa et al also showed that, six months following intra-
articular infiltration of PRGF in patients with OA of the
knee, function, and quality of life improvements were
acknowledged by OA-specific and general clinical assess-
ment instruments.
The results of all these studies indicate that, PRGF, despite
being effective on improving the symptoms of the patients,
may not have superior efficacy in comparison with HA over 6
months, while in the longer duration, it can significantly
increase the patient’s physical function and satisfaction com-
pared with HA.
Some studies have reported several contrary results to
ours. In this regard, Filardo et al reported that, both
groups had clinical improvement at follow-up evaluation,
but the comparison between these two groups showed no
statistically significant difference in all scores
evaluated.
36,48
In the study by Sanchez et al, the rate of
response to PRGF-Endoret was 14.1% higher than that of
Table 3 Lequesne Mean Scores at Baseline, and at the 2nd, 6th, and 12th Months After Injection
Lequesne Index
Pain MWD ADL Total
PRGF HA PRGF HA PRGF HA PRGF HA
Baseline 5.10±1.4 5.12±1.2 1.60±0.8 1.50±.0.9 5.60±0.8 5.60±0.9 12.33±2.4 12.20±2.6
At 2nd m 3.80±1.5 3.70±1.3 1.20±0.7 1.20±0.6 4.40±1.3 4.80±1.1 9.50±3.1 9.80±2.7
At 6th m 3.40±1.7 3.80±1.5 1.30±1.01 1.30±0.7 4.10±1.5 4.80±1.0 8.90±3.6 10.10±3.01
At 12th m 3.70±1.4 4.50±1.5 1.70±1.2 1.70±0.8 4.70±1.3 5.30±1.1 10.20±3.4 11.60±3.0
Mean difference −1.4±1.1 −0.6±1.3 0.10±0.1 0.20±0.7 −0.9±1.2 −0.3±1.2 −2.1±2.9 −0.6±2.9
P-value Within groups P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001
P-value Between groups
b
<0.0001
b
<0.0001
a
0.009
b
<0.0001
Notes:
a
Lequesne activities of daily Life (ADL) at the sixth month.
b
Pain, ADL and Global score at the 12th month.
Abbreviations: HA, hyaluronic acid; MWD, maximum walking distance; PRGF, plasma rich in growth factor.
Figure 2 Means of WOMAC total scores at baseline, and at the 2nd, 6th, and 12th months after injection. PRGF, plasma rich in growth factor; WOMAC, Western Ontario
and McMaster Universities Osteoarthritis Index; HA, hyaluronic acid.
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HA (95% CI, 0.5–27.6; P = 0.044). Regarding the sec-
ondary outcome measures, the rate of response to PRGF-
Endoret was higher than that of HA in all the cases;
however, the difference did not reach statistical
significance. In another study by Montañez-Heredia E,
both PRP and HA treatments improved pain in knee
osteoarthritis patients with no statistically significant dif-
ferences between them.
Figure 3 Mean values of Lequesne total at baseline, and at the 2nd, 6th, and 12th months after injection. PRGF, plasma rich in growth factor; HA, hyaluronic acid.
Figure 4 Means of VAS at baseline, and at the 2nd, 6th, and 12th months after injection.
Abbreviations: PRGF, plasma rich in growth factor; VAS, visual analog scale; HA, hyaluronic acid.
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Different factors should be considered when comparing the
results of studies that have contradicted our study. Variations in
results could have resulted from the preparation techniques
(frequency/speed/length of centrifugation or the use of ancil-
lary activating/anticoagulant agents). There are some ways of
extracting plasma products such as PRP and PRGF. Also,
different methods and concentrations exist, which result in
different end products even though they have similarities in
their names.
58
Accordingly, this difference is largely related to
the concentration of platelets, leukocytes, and growth factors,
all of which are responsible for the effectiveness on converting
a joint destructive environment into repairing or regenerating
status. Moreover, production of PRGF was used, which
employs triple centrifuges to clear the end product of any cell
or material except growth factors.
Another factor is the type of administration techniques
(volume/frequency/delivery regarding means of administra-
tion), as well as post-administration rehabilitation protocols.
In a wide variety of studies performed, there has been a variety
of injections from one injection to multiple, along with weekly
to every 3 or 4 week schedules.
59,63
As observed in other
studies, no general agreement exists among the researchers
regarding a standard frequency of injections. Therefore,
according to our previous plasma product experiences
26,33
and while trying to maintain a balance between these 2 groups
regarding the costs as well, a two-injection schedule was
selected. Follow-up duration is another differentiating factor
among these studies. A large number of researchers claimed
that, there is no difference between HA and plasma products
until two and six months post-injection, while the important
difference was observed at the 12 month post-injection. Other
factors such as baseline characteristics (age, sex, activity level
or OA grade) also affect the results.
36,46,64
Limitation
Our study’sfirst limitation was having no placebo group,
which could mean that, there is no clear evidence that
PRGF is indeed effective on the degenerative cartilage
lesions. Most (75%) of the overall treatment effect on
OA RCTs can be due to contextual effects rather than to
the specific effect of treatments.
65
Failing to blind subjects was another limitation that was
due to the extraction of PRGF from patient blood samples and
different injection schedules. Also it was possible, but not
ethical to take blood from the patients and then to throw
away the collected blood in the HA group. It was insisted by
the ethics committee that blood should not be collected from
the subjects in the HA group. However, the data analyst as well
as the physician performing follow-up interviews and visits,
were kept blinded to the allocation.
Conclusion
In conclusion, our study demonstrate that, besides
a significantly higher satisfaction in the PRGF group,
there was a statistically significant improvement after 12
months post-injection in VAS score and global, pain, and
ADL score of Lequesne test in PRGF compared to HA.
Data Sharing Statement
•Whether the authors intend to share the individuals’
deidentified participant data;
Yes
•What specific data they intend to share;
Deidentified data including individual test results and
demographic features data.
•What other study-related documents will be made
available;
None
•How the data will be accessible;
Data can be shared after a direct contact with IRB and
receiving their permission.
•When and for how long they will be made available.
Until 3 years after publishing the results.
Acknowledgments
The abstract of this paper was presented at the EULAR
2019 Annual European Congress of Rheumatology as
a poster presentation/conference talk with interim findings.
The poster’s abstract was published in ‘Poster Abstracts’
in Annals of Rheumatic Diseases: https://ard.bmj.com/con
tent/78/Suppl_2/499.1
The authors would like to thank their dear colleagues
from the Physical Medicine and Rehabilitation Research
Center and Clinical Research Developmental Center of
Shahid Moddares Hospital, Mehrnaz Mehrabi for her
Table 4 Rate of the Patient’s Satisfaction 12 Months Post-Injection
PRGF HA P-value Statistical
Test
Very Poor 11 (21.6%) 5(9.8%) 0001> Mann–Whitney
Poor 7 (13.7%) 22 (43.1%)
Regular 11 (21.6%) 10 (19.6%)
Good 17 (33.3%) 6 (11.8%)
Very Good 11 (21.6%) 2 (3.9%)
Abbreviations: HA, hyaluronic acid; PRGF, plasma rich in growth factor
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cooperation in data collection. This article has been
extracted from the thesis written by Dr. Pegah Yavari in
the School of Medicine of Shahid Beheshti University of
Medical Sciences.
Disclosure
The authors report no conflicts of interest in this work.
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