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Autologous Growth Factor Injections in Chronic Tendinopathy SR

This document summarizes a systematic review of studies examining the effects of injections with autologous whole blood or platelet-rich plasma (PRP) in the management of chronic tendinopathies. The review found that while injections of autologous growth factors showed improvements in pain and function over time, only a few studies of injections with autologous whole blood were high quality, and none showed benefit compared to a control group. There was also limited evidence for the use of PRP injections. More high-quality research is needed to determine the effectiveness of these treatments.

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0% found this document useful (0 votes)
14 views15 pages

Autologous Growth Factor Injections in Chronic Tendinopathy SR

This document summarizes a systematic review of studies examining the effects of injections with autologous whole blood or platelet-rich plasma (PRP) in the management of chronic tendinopathies. The review found that while injections of autologous growth factors showed improvements in pain and function over time, only a few studies of injections with autologous whole blood were high quality, and none showed benefit compared to a control group. There was also limited evidence for the use of PRP injections. More high-quality research is needed to determine the effectiveness of these treatments.

Uploaded by

majd.rezkallah
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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Published Online March 2, 2010

Autologous growth factor injections in chronic


tendinopathy: a systematic review

R. J. de Vos *, P. L. J. van Veldhoven, M. H. Moen, A. Weir, J. L. Tol, and


N. Maffulli
Department of Sports Medicine, The Hague Medical Centre Antoniushove, Leidschendam,
The Netherlands

Chronic degenerative tendinopathies are frequent and difficult to treat. Tendon

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healing and regeneration may be improved by injecting autologous growth
factors obtained from the patient’s blood. Autologous growth factors can be
injected with autologous whole blood or platelet-rich plasma (PRP). Electronic
databases were searched for prospective clinical trials on treatment with
autologous growth factors of patients with chronic tendinopathy. Chronic
tendinopathy in this study included wrist extensors, flexors, plantar fasciopathy
and patellar tendinopathy. Studies examining the treatment of other
tendinopathies were not identified. The Physiotherapy Evidence Database score
was used to examine the methodological quality of the assessment, and a
qualitative analysis was performed with the levels of evidence. There are many
proposed treatment options for chronic tendinopathy. Treatments in the form of
injections with autologous whole blood or PRP are increasingly used in clinical
practice. There are high expectations of these regenerative injections, and there
is a clear need for effective conservative therapies. All studies showed that
injections of autologous growth factors (whole blood and PRP) in patients with
chronic tendinopathy had a significant impact on improving pain and/or
function over time. However, only three studies using autologous whole blood
had a high methodological quality assessment, and none of them showed any
benefit of an autologous growth factor injection when compared with a control
group. At present, there is strong evidence that the use of injections with
autologous whole blood should not be recommended. There were no high-
quality studies found on PRP treatment. There is limited evidence to support the
Accepted: January 16, use of injections with PRP in the management of chronic tendinopathy. There is
2010
growing interest in the working mechanisms of autologous growth factors. The
*Correspondence address.
Department of Sports amount and mixture of growth factors produced using different cell separating
Medicine, The Hague systems are largely unknown and it is also uncertain whether platelet activation
Medical Centre prior to injection is necessary. These variables should be taken into account
Antoniushove, PO Box
411, Burgemeester
when starting clinical studies. A good experimental model for studying
Banninglaan 1, 2260 AK tendinopathy would be helpful for basic research. Future clinical studies using a
Leidschendam, The proper control group, randomization, blinding and validated disease-specific
Netherlands. E-mail:
outcome measures for pain and function are needed.
[email protected]

British Medical Bulletin 2010; 95: 63–77 & The Author 2010. Published by Oxford University Press. All rights reserved.
DOI:10.1093/bmb/ldq006 For permissions, please e-mail: [email protected]
R. J. de Vos et al.

Keywords: tendinopathy/tendon/autologous growth factors/autologous


blood/platelet-rich plasma/injection therapy

Introduction
Chronic painful tendon disorders are common in athletic and sedentary
individuals.1 – 4 They are more common in middle age, and with
increasing in sports participation at increasing ages, they are becoming
more frequent.1,2 The Achilles tendon, patella tendon, wrist extensors,
plantar fascia and supraspinatus tendon are commonly affected larger
tendons.5 Multiple aetiological factors probably play a role in the
pathogenesis of these conditions.1 – 5

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If the triad of pain, swelling and a reduced load bearing capacity are
present, then the correct term for the diagnosis is tendinopathy.1 This
is a clinical and not a histopathological diagnosis.1,3 A failed healing
repair process at tissue level results in a variety of histopathological
changes, including degeneration, of the tendon tissue.3 Tendinopathy
leads to a reduction in activity levels and sometimes to cessation of all
sporting activities.4
Increasing knowledge of the pathology and pathogenesis of tendino-
pathy has lead to the introduction of a large number of conservative
treatments. At present, the best available evidence points towards the
use of heavy load eccentric training programmes.6 Conventional con-
servative therapy is ineffective in around 25% of patients with Achilles
tendinopathy.7 In these patients, surgery can be performed, but it is
not always successful, and the post-operative rehabilitation is slow and
time consuming.3,4,6 – 8 To reduce the need for surgery, more effective
conservative therapies are needed.
Recently, research has focused on regenerative therapies with high
expectations of success.9,10 The use of autologous growth factors is
thought to lead to tendon healing through collagen regeneration and
the stimulation of a well-ordered angiogenesis.9,10 These growth
factors are administered in the form of autologous whole blood or
platelet-rich plasma (PRP).9 Platelets can be isolated using simple cell-
separating systems.9,11 The degranulation of the a-granules in the plate-
lets releases many different growth factors that play a role in tissue
regeneration processes. Platelet-derived growth factor, transforming
growth factor-b, vascular-derived endothelial growth factor, epithelial
growth factor, hepatocyte growth factor and insulin-like growth factor
are examples of such growth factors.9 – 12 Injections with autologous
growth factors are becoming common in clinical practice.10,11
This systematic review examines the literature on the effects of auto-
logous blood and PRP injections in the management of tendinopathies.

64 British Medical Bulletin 2010;95


Autologous growth factors in chronic tendinopathy

Methods
Literature search
A comprehensive, systematic literature search was performed in
October 2009. The databases of PubMed, MEDLINE, EMBASE,
CINAHL and the Cochrane library were searched without time limits.
The following key words were used in differing combinations: ‘tendino-
pathy’, ‘tendinosis’, ‘tendinitis’, ‘tendons’, ‘tennis elbow’, ‘plantar fas-
ciitis’, ‘platelet rich plasma’, ‘platelet transfusion’, ‘autologous blood’
or ‘injection’. The search was limited to articles in English, and only
human studies were included. All titles and abstracts were assessed by
two researchers, and all relevant articles were obtained. All bibliogra-

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phies were also hand searched to identify further relevant literature.
All relevant articles were read independently in full text by two
researchers to assess whether they met the inclusion criteria. If there
was a difference in opinion on suitability, a consensus was reached by
consulting a third reviewer.

Study selection
Articles were suitable (inclusion criteria) if the subjects had been clini-
cally diagnosed as having chronic tendinopathy. The design had to be a
prospective clinical study; randomized controlled trial (RCT), non-
randomized clinical trial (CCT) or prospective case series. There had to
be a well-described intervention in the form of an injection with either
PRP or autologous blood. The outcome had to be reported in terms of
pain and/or function.

Data extraction
Two researchers independently recorded the study design, population,
intervention, outcome measure and outcome using standardized data
extraction forms.13 To assess the efficacy of the interventions, mean
values of the continuous outcomes were extracted from the published
articles.

Quality assessment
The studies included were scored using the PEDro (Physiotherapy
Evidence Database) score.14 The PEDro score is an 11-point list using
yes and no answers. The first statement pertains to the external validity

British Medical Bulletin 2010;95 65


R. J. de Vos et al.

Table 1 PEDro scale.

Items

1. Eligibility criteria were specified


2. Subjects were randomly allocated to groups
3. Allocation was concealed
4. The groups were similar at baseline regarding the most important prognostic indicators
5. There was blinding of all subjects
6. There was blinding of all therapists who administered the therapy
7. There was blinding of all assessors who measured at least one key outcome
8. Measures of at least one key outcome were obtained from more than 85% of the subjects initially
allocated to groups
9. All subjects for whom outcome measures were available received the treatment or control condition
as allocated or, where this was not the case, data for at least one key outcome were analysed by
‘intention to treat’
10. The results of between-group statistical comparisons are reported for at least one key outcome

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11. The study provides both point measures and measures of variability for at least one key outcome

The score is the number of positive answers on questions 2 –11 (0 – 10).

of the study and is not used to compute the final quality score. The
score (0– 10) is the number of positive answers on questions 2– 11. The
PEDro items are shown in Table 1.
To assess the reliability of consensus ratings using the PEDro scale, a
study was conducted by Maher et al.14 A random selection of 120
RCTs was assessed four times by four different raters. Intraclass corre-
lation coefficient for consensus ratings using the PEDro scale showed
to be 0.68, which compares to a ‘fair’ to ‘good’ reliability.15 It was
suggested that the PEDro scale has sufficient reliability for its use in
systematic reviews of physiotherapy trials,14 and recently it has been
used in a systematic review on the effects of exercise treatment in
tendinopathy.16
A PEDro score of 6 or higher is considered to represent a high-quality
study.16 The results of the quality assessments of the individual trials
were used to classify the level of evidence.17 This qualitative analysis
was performed with five levels of evidence based upon the quality and
results of clinical studies:

1. strong evidence: provided by generally consistent findings in multiple high-


quality RCTs
2. moderate evidence: provided by generally consistent findings in one high-
quality RCTs and one or more lower-quality RCTs, or by generally con-
sistent findings in multiple low-quality RCTs
3. limited evidence: provided by only one RCT (either high or low quality)
or generally consistent findings in CCTs
4. conflicting evidence: inconsistent findings in multiple RCTs or CCTs
5. no evidence: no RCTs or CCTs

66 British Medical Bulletin 2010;95


Autologous growth factors in chronic tendinopathy

Studies with a high methodological score using the PEDro scale were
considered as high-quality studies and those with a low PEDro score
were considered low-quality studies.

Results
Literature search
Thirteen studies were included after screening. Two studies were
excluded (figure 1).43,44 Eleven studies were suitable for quality assess-
ment and were assessed using the PEDro score.

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Study design
There were six observational non-controlled studies18 – 23 and five con-
trolled clinical trials24 – 28 of which two were evaluated as having
appropriate randomisation.24,28

Participants
The mean number of subjects was 40.5 (SD 24.6) with a range 20–
100. Four studies were on patients with chronic tendinopathy of the
wrist extensors (tennis elbow)18,19,23,25 of which one study on both
wrist extensor and flexor tendinopathy (golfer’s elbow).25 One study
evaluated the treatment effect on tendinopathy of wrist flexors.20
Patients with chronic plantar fasciopathy were treated in three
studies24,27,28 and three studies had examined patients with chronic
patellar tendinopathy.21,22,26

Interventions
There were eight studies on the effects of autologous blood injec-
tions,18 – 21,23,24,27,28 of which five studies used this in combination
with a local anaesthetic18 – 21,24 and the other three studies applied only
autologous blood.23,27,28
There were three studies on PRP injections,22,25,26 of which one used
an additional local anaesthetic25 and two did not report whether local
anaesthesia was used.22,26 In three studies a single injection,24,25,27 in
one study two injections21 and in two studies three injections22,26 were
used. In the other five studies, a varying number of injections (1 –3)
were given.18 – 20,23,28 The PRP was prepared using a single25 or
double22,26 centrifuging process. In two studies, calcium was added to
the PRP for activation of the platelets.22,26

British Medical Bulletin 2010;95 67


R. J. de Vos et al.

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Fig. 1 QUOROM statement flow diagram.

Outcome measures
Ten of the 11 studies used a visual analogue scale or ordinal scale to
measure pain.18 – 20,22 – 28 In four studies, the elbow function was quan-
tified using the Nirschl score.18 – 20,23 The Nirschl score runs from 1;

68 British Medical Bulletin 2010;95


British Medical Bulletin 2010;95

Table 2 Included studies.

Reference Number of Study Inclusion Intervention Control group(s) Primary outcome Follow-up Outcome in Outcome in control
participants design criteria measures (months) intervention group(s) (%
group (% improvement)
improvement)

Edwards and 28 Case series Wrist extensor 1 –3 autologous — Pain scale (0 –10) 9.5 Mean pain score: —
Calandruccio18 tendinopathy blood 7.8 to 2.3 (71%)
injection(s)
Nirschl score (0 –7) Mean Nirschl
score: 6.5 to 2.0
(69%)
Mishra and 20 CCT Wrist extensor 1 PRP injection C: 1 anaesthetic VAS score (0 –100) 25.6 Mean VAS score: C: Mean VAS score:
Pavelko25 and flexor injection 80.3 to 5.7 NA
tendinopathy (93%)
Modified Mayo Mean Modified Mean Modified
elbow score (0 – 100) Mayo elbow Mayo elbow score:
score: NA NA
Suresh et al.20 20 Case series Wrist flexor 2 –3 autologous — VAS score (0 –10) 10 Mean VAS score: —
tendinopathy blood injections 8.0 to 2.2 (73%)
Nirschl score (0 –7) Median Nirschl
score: 6.0 to 1.0
(83%)
Connell et al.19 35 Case series Wrist extensor 2 –3 autologous — VAS score (0 –10) 6 Median VAS —
tendinopathy blood injections score: 9.0 to 0.0

Autologous growth factors in chronic tendinopathy


(100%)
Nirschl score (0 –7) Median Nirschl
score: 6.0 to 0.0
(100%)
Kiter et al.28 54 RCT Plantar 1 –3 autologous C1: 1 –2 VAS score (0 –10) 6 Mean VAS score: C1: Mean VAS score:
fasciopathy blood corticosteroid 7.6 to 2.4 (68%) 7.3 to 2.6 (65%)†
injection(s) injection(s)
C2: dry needling AOFAS score (0 –100) Mean AOFAS Mean AOFAS score:
score: 71.6 to 65.7 to 80.1 (42%)†
80.9 (33%)
C2: Mean VAS score:
6.4 to 2.0 (69%)†
Mean AOFAS score:
64.1 to 78.2 (39%)†
Ul Gani et al.23 26 Case series Wrist extensor 1 –2 autologous — Pain scale (1 –4) 8 Mean pain score: —
tendinopathy blood 3.3 to 1.2 (64%)
injection(s)
69

Continued

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70

R. J. de Vos et al.
Table 2 Continued

Reference Number of Study Inclusion Intervention Control group(s) Primary outcome Follow-up Outcome in Outcome in control
participants design criteria measures (months) intervention group(s) (%
group (% improvement)
improvement)

Nirschl score (0 –7) Mean Nirschl


score: 5.5 to 2.1
(62%)
James et al.21 47 Case series Patellar 2 autologous — VISA-P score (0 –100) 14.8 Mean VISA-P —
tendinopathy blood injections score: 39.8 to
combined with 74.3 (57%)
dry needling
Lee and 64 RCT Plantar 1 autologous C: 1 corticosteroid VAS score (0 –10) 6 Mean VAS score: C: Mean VAS score:
Ahmad24 fasciopathy blood injection injection 7.3 to 3.6 (51%) 6.9 to 2.4 (65%)†
Kon et al.22 20 Case series Patellar 3 PRP injections — EQ-VAS score 6 Mean EQ-VAS —
tendinopathy (0 –100) score: 57 to 82
(58%)
Tegner score (0– 10) Mean Tegner
score: 4 to 7
(50%)
Filardo et al.26 31 CCT Patellar 3 PRP injections C: exercise therapy EQ-VAS score 6 Mean EQ-VAS C: Mean EQ-VAS
tendinopathy (0 –100) score: 52.7 to score: 50.6 to 73.5
78.3 (54%) (46%)†
Tegner score (0– 10) Mean Tegner Mean Tegner score:
score: 3.7 to 6.6 5.3 to 6.8 (32%)*
(46%)
Kalaci et al.27 100 CCT Plantar 1 autologous C1: 1 corticosteroid VAS score (0 –10) 6 Mean VAS score: C1: Mean VAS score:
fasciopathy blood injection injection 6.8 to 3.5 (48%) 7.0 to 1.5 (78%)‡
C2: 1 corticosteroid C2: Mean VAS score:
injection 7.2 to 1.0 (87%)‡
combined with dry
needling
British Medical Bulletin 2010;95

C3: 1 anaesthetic C3: Mean VAS score:


injection 6.7 to 3.4 (48%)†
combined with dry
needling

Improvements were calculated after correcting for scale and baseline score. CCT, non-randomized clinical trial; RCT, randomized controlled trial; VAS, visual analogue scale;
VISA-P, Victorian Institute of Sports Assessment-Patella; AOFAS, American Orthopaedics Foot and Ankle (rearfoot score); NA, not available; C, control group. *Significant
improvement in favour of autologous growth factor injection. †No significant difference with control group. ‡Significant improvement in favour of control group.

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Autologous growth factors in chronic tendinopathy

mild pain during activity to 7; constant pain at rest. To our knowledge,


there are no data available on the validity of the Nirschl score. One
study21 used the Victorian Institute of Sports Assessment-Patella
(VISA-P) score which is a validated outcome measure for patellar tendi-
nopathy that assesses pain and function. It runs from 0 representing
maximal pain and minimal function to 100 which represents no pain
and maximal functioning. The two other studies on patellar tendinopa-
thy used the Tegner score to quantify activity level.22,26 The Tegner
score runs from 0 to 10 with 0 being invalidated and 10 representing
specific professional sports activities. The Tegner score previously
showed an acceptable validity in the evaluation of meniscal injuries.29
One study on plantar fasciopathy used the rearfoot score of the
American Orthopaedics Foot and Ankle (AOFAS) to assess function.28

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There are no data available on the validity of the AOFAS score for the
evaluation of plantar fasciopathy. This score runs from 0 to 100; a
score of 100 represents no pain and optimal functioning. One study
used the modified Mayo elbow score, which was not recorded at final
follow-up.25

Outcomes
All the intervention groups reported a significant improvement in the
pain and/or function scores with the mean improvement being 66%
(SD 19, range 33– 100). The outcomes in the control groups also
improved significantly in all the studies with a mean improvement of
57% (SD 18, range 32 –87). These improvements were reported after a
mean follow-up of 9.4 months (SD 6.0). There was in none of the
included studies a beneficial effect on pain score at final follow-up
after autologous growth factor injections when compared with a
control group.24,26 – 28 One study reported a significant improvement
on the functional Tegner score when compared with the control group,
but the statistical baseline difference in Tegner score between these
groups was not reported.26 In four other control groups, there were
similar results on pain and/or function when compared with autolo-
gous growth factor injections.24,27,28 In two control groups, there was
a significant improvement on pain in favour of the control group.27
Table 2 gives an overview of these differences.

Sample-size calculation
Only one trial reported a sample-size calculation.22 Kon et al. reported
that 20 cases were needed to detect a clinically important increase of

British Medical Bulletin 2010;95 71


R. J. de Vos et al.

Table 3 Particular scoring of the included studies for methodological quality according to
the PEDro score.

Reference Item PEDro score Total score

1 2 3 4 5 6 7 8 9 10 11
18
Edwards and Calandruccio þ 2 2 2 2 2 2 þ þ 2 2 2/10
Mishra and Pavelko25 þ 2 2 2 2 2 2 2 2 þ þ 2/10
Suresh et al.20 þ 2 2 2 2 2 2 2 2 2 þ 1/10
Connell et al.19 þ 2 2 2 2 2 2 2 2 2 þ 1/10
Kiter et al.28 þ þ 2 þ 2 2 þ þ þ þ þ 7/10
Ul Gani et al.23 þ 2 2 2 2 2 2 þ þ 2 2 2/10
James et al.21 þ 2 2 2 2 2 2 þ 2 2 þ 2/10
Lee and Ahmad24 þ þ 2 þ 2 2 þ þ þ þ þ 7/10
Kon et al.22 þ 2 2 2 2 2 2 þ þ 2 þ 3/10
Filardo et al.26 þ 2 2 2 2 2 2 þ þ þ þ 4/10

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Kalaci et al.27 þ 2 2 2 þ 2 þ þ þ þ þ 6/10

The total score was defined by the number of positive answers on questions 2–11 (0 –10).

15 points on the VAS score. All other included studies did not report
using a sample-size calculation.

Methodological quality
The PEDro scores for the 11 studies are shown in Table 3. The scores
ranged from 1 to 7 with an average of 3.4 (SD 2.3). Three studies were
considered as being high quality (PEDro score  6) and the other eight
studies were of low quality (PEDro score , 6). All the studies reported
the inclusion criteria. A comparison to another treatment was per-
formed in five studies, and randomization was used in two studies.
Blinding of the treatment was undertaken for patients in one study,27
for the treating physician in none of the studies and for the outcome
assessor in three studies.24,27,28 In three studies, more than 15% of the
patients were lost to follow-up,19,20,25 and in four studies, the data
analysis was not performed on an ‘intention to treat’ basis.19 – 21,25
Two studies had poor reporting of the statistical analysis.18,23

Level of evidence
Until now, three high-quality studies24,27,28 on the use of autologous
growth factor injections (all used autologous blood injections) for the
management of chronic tendinopathy showed no significant improve-
ment when compared with a control group. One study showed a sig-
nificantly superior improvement after a corticosteroid injection in
comparison with one single autologous blood injection.27 Two of these

72 British Medical Bulletin 2010;95


Autologous growth factors in chronic tendinopathy

high-quality studies were RCTs. As such, there is level 1 (strong) evi-


dence of no improvement in pain and/or function in chronic tendinopa-
thy after injecting autologous blood when compared with other
treatment options. If PRP injections were to be considered separately,
three low-quality studies were included, and so there is level 3 (limited)
evidence that these injections improve pain and/or function in chronic
tendinopathy.

Discussion
A total of 11 articles were suitable for inclusion in this systematic
review on the use of autologous growth factors in the treatment of

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chronic tendinopathy. Three studies, of which two were RCTs, were of
high quality. All studies showed an improvement in pain and function
scores, but there was no difference when compared with the improve-
ment in pain scores in the control groups. After a qualitative analysis,
there was level one (strong) evidence that injections with autologous
blood were not of benefit. Currently, there is level 3 (limited) evidence
that PRP injections improve pain and/or function in chronic
tendinopathy.
These findings are clinically relevant, as the use of autologous growth
factors is gaining popularity.9 – 11 This results in part from laboratory
studies showing positive and promising results.30 – 32 Autologous
growth factors have the potential to change collagen production and
degradation by influencing matrix regulating enzymes.9,10,33
Laboratory studies showed that the addition of PRP to human teno-
cytes resulted in cell proliferation, collagen deposition and improved
gene expression for matrix degrading enzymes and endogenous growth
factors.30 A recent animal study found similar results,31 and the in vivo
application of PRP suggested an accelerated remodelling and angio-
genic process. Bosch et al.32 performed a placebo-controlled ultrasound
study on the recovery of horse tendons using PRP which showed an
increase in anti-inflammatory response and fibrillogenesis in the short
term. At longer-term follow-up, an increased, collagen matrix integrity
was found in the PRP treated tendons.
Although the results of laboratory studies are encouraging, they
always use healthy tendons or surgically induced lesions given the lack
of a good experimental model for tendinopathy. At present, it is unclear
whether these results can be extrapolated to tendinopathic tendons, and
future research in the field of basic science should study this.
This systematic review makes it clear that there is a lack of good
quality studies in this field, especially regarding treatment with PRP.
The commonest methodological flaws are the lack of a suitable control

British Medical Bulletin 2010;95 73


R. J. de Vos et al.

group, randomization and blinding of subjects and those involved in


the treatment. One research group reported that the study design was a
RCT,27 but after critically reading the full-text, it became apparent that
this study was a CCT. Another research group selected a very small
control group of five patients and reported a significant improvement
in pain and function scores in the PRP group compared with this small
control group after 8 weeks.25 However, the patients in the control
group were lost to follow-up already after 8 weeks and could not be
included in the final analysis. Although there was a consensus that this
was a CCT, the authors agreed that the control group was not appro-
priate. Although these methodological processes are relatively simple to
implement, it does make the research process more intensive and less
attractive for potential subjects. It is not uncommon for pilot studies to

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be performed to assess the effect size of new treatments before progres-
sing to evaluate their use in randomized controlled clinical trials.
Lower-quality studies on the management of tendinopathy evidence
better results than good-quality studies.34 Future studies should there-
fore use appropriate randomization, and all those involved should be
blinded to the treatment given.
A few other suggestions on future research can also be made. There
may be differences in natural healing response between load-bearing
tendons, such as the patellar and Achilles tendon, and non-load-bearing
tendons, such as the wrist extensors and flexors. Wrist extensor tendi-
nopathy is a self-limiting disease with 80 –90% recovery within 1
year,35 whereas patients with tendinopathy of the main body of the
Achilles tendon did not improve in a trial with a four month wait and
see arm.36 In some studies, the subjects included had a variety of mid-
portion and insertional tendinopathies, and it is unclear whether these
can be compared, as these portions of the tendon have differing biome-
chanical and metabolic properties and responses to treatment.5 This
makes comparing the results of studies on differing locations of tendi-
nopathy difficult and emphasizes the need of suitable control groups.
Many of the studies on the effect of injections with autologous
growth factors used a mixture with local anaesthetic which could lead
to bias, as an injection with local anaesthetic alone led to improvement
in a previous trial on elbow tendinopathy.35
Most of the studies included in this review used pain as the primary
outcome to assess treatment effect. Only one study had used the
VISA-P score, a validated outcome questionnaire for patellar tendino-
pathy. Four studies used the Nirschl score, which does give a global
impression of pain in combination with activity. Outcome assessment
should focus on activity as well as pain when studying tendinopathy
and where possible use disease-specific validated measures.37 Another
important feature of outcome assessment is the prior establishment of

74 British Medical Bulletin 2010;95


Autologous growth factors in chronic tendinopathy

the minimally important clinical difference. Only one study of those


included reported a sample size calculation with the use of a clinically
relevant difference.22 In osteoarthritis research, minimally important
clinical differences are defined for different outcome measures,38 but
these values are lacking in tendinopathy research.
No studies to date have compared an injection with autologous
growth factors to a placebo injection. The effects of placebo treatments
are greater the more invasive they are,39 and a recent tendinopathy
study showed a large effect after a placebo injection was performed.40
Currently, there have also been no studies that have compared autolo-
gous blood to PRP. This would be interesting given the larger costs and
practical difficulties associated with preparing PRP.
Along with treatment effects it is also necessary to report and

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monitor for complications.33 In the studies included here, no compli-
cations were reported but it is important to monitor for infections, rup-
tures and possible systemic effects when using autologous growth
factors.
There are still many unanswered questions in this field. There has
been little research performed on the amount of growth factors pro-
duced using different cell separating systems, and what the optimal
mixture would be.10,11 It is unclear what the best volume and fre-
quency of the injections is. Moreover, when multiple injections are con-
sidered, the ideal period between multiple injections is unknown. It is
also uncertain whether platelet activation prior to injection is necess-
ary, as contact with collagen would also lead to platelet
degranulation.41,42

Conclusion
There is strong evidence that autologous blood injections do not
improve pain and/or function compared with other treatment options.
There is only limited evidence that PRP injections are beneficial. All
three high-quality studies on the use of autologous growth factor injec-
tions in the management of chronic tendinopathy showed no benefit.
All studies did show an effect on pain and function in time, but many
are seriously methodologically flawed. To date, there is strong evidence
that the use of injections with autologous blood should not be rec-
ommended, and there is limited evidence to support the use of injec-
tions with PRP in the treatment of chronic tendinopathy. Further
studies using a proper control group, randomization, blinding and vali-
dated disease-specific outcome measures for pain and function are
needed.

British Medical Bulletin 2010;95 75


R. J. de Vos et al.

References
1 Maffulli N, Wong J, Almekinders LC. Types and epidemiology of tendinopathy. Clin Sports
Med 2003;22:675– 92.
2 Schepsis AA, Jones H, Haas AL. Achilles tendon disorders in athletes. Am J Sports Med
2002;30:287–305.
3 Alfredson H. Chronic midportion Achilles tendinopathy: an update on research and treat-
ment. Clin Sports Med 2003;22:727– 41.
4 van Linschoten R, den Hoed PT, de Jongh AC. Guideline ’Chronic Achilles tendinopathy, in
particular tendinosis, in sportsmen/sportswomen’. Ned Tijdschr Geneeskd 2007;151:2319–24.
5 Woo SLY, Renstró´m PAFH. Tendinopathy in Athletes, the Encyclopaedia of Sports Medicine,
Vol. XII. Hong Kong: Blackwell Publishing, 2007,1– 9.
6 Andres BM, Murrell GA. Treatment of tendinopathy: what works, what does not, and what
is on the horizon. Clin Orthop Relat Res 2008;466:1539– 54.
7 Kvist M. Achilles tendon injuries in athletes. Sports Med. 1994;18:173–201.
8 Zwerver J. Patellar tendinopathy (‘jumper’s knee’); a common and difficult-to-treat sports

Downloaded from http://bmb.oxfordjournals.org/ by guest on December 1, 2013


injury. Ned Tijdschr Geneeskd 2008;16:1831– 7.
9 Sampson S, Gerhardt M, Mandelbaum B. Platelet rich plasma injection grafts for musculos-
keletal injuries: a review. Curr Rev Musculoskelet Med 2008;1:165– 74.
10 Mishra A, Woodall J Jr, Vieira A. Treatment of tendon and muscle using platelet-rich
plasma. Clin Sports Med 2009;28:113– 25.
11 Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates:
from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends
Biotechnol 2009;27:158–67.
12 Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from
platelet-rich plasma: implications for wound healing. Plast Reconstr Surg 2004;114:1502– 8.
13 Moher D, Cook DJ, Eastwood S et al. Improving the quality of reports of meta-analyses of
randomised controlled trials: the QUOROM statement. Quality of Reporting of
Meta-analyses. Lancet 1999;354:1896–900.
14 Maher CG, Sherrington C, Herbert RD et al. Reliability of the PEDro scale for rating quality
of randomized controlled trials. Phys Ther 2003;83:713– 21.
15 Fleiss JL. The Design and Analysis of Clinical Experiments. New York, NY: John Wiley &
Sons Inc., 1986.
16 Woodley BL, Newsham-West RJ, Baxter GD. Chronic tendinopathy: effectiveness of eccentric
exercise. Br J Sports Med 2007;41:188– 98.
17 van Tulder M, Furlan A, Bombardier C et al. Editorial Board of the Cochrane Collaboration
Back Review Group. Updated method guidelines for systematic reviews in the cochrane col-
laboration back review group. Spine (Phila Pa 1976) 2003;28:1290– 9.
18 Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral epicondyli-
tis. J Hand Surg [Am] 2003;28:272–8.
19 Connell DA, Ali KE, Ahmad M et al. Ultrasound-guided autologous blood injection for
tennis elbow. Skeletal Radiol 2006;35:371– 7.
20 Suresh SP, Ali KE, Jones H et al. Medial epicondylitis: is ultrasound guided autologous blood
injection an effective treatment? Br J Sports Med 2006;40:935– 9.
21 James SL, Ali K, Pocock C et al. Ultrasound guided dry needling and autologous blood injec-
tion for patellar tendinosis. Br J Sports Med 2007;41:518–21.
22 Kon E, Filardo G, Delcogliano M et al. Platelet-rich plasma: new clinical application: a pilot
study for treatment of jumper’s knee. Injury 2009;40:598– 603.
23 Ul Gani N, Butt M, Dhar SA et al. Autologous Blood Injection In The Treatment Of
Refractory Tennis Elbow. Internet J Orthop Surg 2007;5.
24 Lee TG, Ahmad TS. Intralesional autologous blood injection compared to corticosteroid
injection for treatment of chronic plantar fasciitis. A prospective, randomized, controlled
trial. Foot Ankle Int 2007;28:984– 90.
25 Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet rich
plasma. Am J Sports Med 2006;34:1774–8.

76 British Medical Bulletin 2010;95


Autologous growth factors in chronic tendinopathy

26 Filardo G, Kon E, Della Villa S et al. Use of platelet-rich plasma for the treatment of refrac-
tory jumper’s knee. Int Orthop 2009. [Epub ahead of print], PMID: 19641918.
27 Kalaci A, Cakici H, Hapa O et al. Treatment of plantar fasciitis using four different local
injection modalities: a randomized prospective clinical trial. J Am Podiatr Med Assoc
2009;99:108– 13.
28 Kiter E, Celikbas E, Akkaya S et al. Comparison of injection modalities in the treatment of
plantar heel pain: a randomized controlled trial. J Am Podiatr Med Assoc 2006;96:293–6.
29 Briggs KK, Kocher MS, Rodkey WG et al. Reliability, validity, and responsiveness of the
Lysholm knee score and Tegner activity scale for patients with meniscal injury of the knee.
J Bone Joint Surg Am 2006;88:698–705.
30 De Mos M, van der Windt AE, Jahr H et al. Can platelet-rich plasma enhance tendon repair?
A cell culture study. Am J Sports Med 2008;36:1171–8.
31 McCarrel T, Fortier L. Temporal growth factor release from platelet-rich plasma, trehalose
lyophilized platelets, and bone marrow aspirate and their effect on tendon and ligament gene
expression. J Orthop Res 2009;27:1033–42.
32 Bosch G, van Schie HT, de Groot M et al. Effects of platelet rich plasma on the quality of

Downloaded from http://bmb.oxfordjournals.org/ by guest on December 1, 2013


repair of mechanically induced core lesions in equine superficial digital flexor tendons: a
placebo-controlled experimental study. J Orthop Res 2010;28:211– 217.
33 Creaney L, Hamilton B. Growth factor delivery methods in the management of sports inju-
ries: the state of play. Br J Sports Med 2008;42:314–20.
34 Tallon C, Coleman BD, Khan KM et al. Outcome of surgery for chronic Achilles tendinopa-
thy. A critical review. Am J Sports Med 2001;29:315–20.
35 Rineer CA, Ruch DS. Elbow tendinopathy and tendon ruptures: epicondylitis, biceps and
triceps ruptures. J Hand Surg [Am] 2009;34:566–76.
36 Rompe JD, Nafe B, Furia JP et al. Eccentric loading, shock-wave treatment, or a wait-and-see
policy for tendinopathy of the main body of tendo Achillis: a randomized controlled trial.
Am J Sports Med 2007;35:374–83.
37 Kingma JJ, de Knikker R, Wittink HM et al. Eccentric overload training in patients with a
chronic Achilles tendinopathy: a systematic review. Br J Sports Med 2007;41:e3.
38 Pham T, van der Heijde D, Altman RD et al. OMERACT-OARSI initiative: Osteoarthritis
Research Society International set of responder criteria for osteoarthritis clinical trials
revisited. Osteoarthr Cartil 2004;12:389–99.
39 Zhang W, Robertson J, Jones AC et al. The placebo effect and its determinants in osteoar-
thritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67:1716–23.
40 Brown R, Orchard J, Kinchington M et al. Aprotinin in the management of Achilles tendino-
pathy: a randomised controlled trial. Br J Sports Med 2006;40:275– 9.
41 Anitua E, Sánchez M, Nurden AT et al. New insights into and novel applications for
platelet-rich fibrin therapies. Trends Biotechnol 2006;24:227–34.
42 Fufa D, Shealy B, Jacobson M et al. Activation of platelet-rich plasma using soluble Type I
collagen. J Oral Maxillofac Surg 2008;66:684–90.
43 Mishra A, Collado H, Fredericson M. Platelet-rich plasma compared with corticosteroid
injection for chronic lateral elbow tendinosis. PM R 2009;1:366–70.
44 Barrett SL, Erredge SE. Growth factors for chronic plantar fasciitis? Podiatry Today
2004;17:36– 42.

British Medical Bulletin 2010;95 77

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