PRP Stem Cell Campinas out2012

PRP e Células Tronco - um novo caminho
para o tratamento de lesões esportivas
HTTP://WWW.NEOESPORTE.COM

WWW.NEO.ORG.BR

Prof. Dr. Rogerio Teixeira da Silva
Coordenador do NEO - Núcleo de Estudos em Esportes e Ortopedia
Hospital Samaritano - São Paulo, Brasil
SBRATE / SBOT

Campinas, SP, Brasil - 26 e 27 de outubro de 2012

and ultimately, finishes with tissue remodeling
takes years.1 PRP preparations contain high con
the Department of Orthopaedics, The Ottawa Hospital
K.A.G., D.A.S.), Ottawa, Ontario, Canada; Arthroscopy tions of platelets that, once activated, undergo d

Introdução
Clinica La Esperanza (M.S.), La Esperanza, Spain; and lation to release growth factors with healing pro
nt of Orthopaedic Surgery, University of Ottawa (D.H.J.), They also contain plasma and other growth fac
Ontario, Canada.
ted by Fundación Caja Madrid. The authors report no plicated in wound healing, in addition to th
f interest. which has inherent biological and adhesive prop
ed September 15, 2009; accepted November 18, 2009.
Current Concepts basic mechanism for preparing PRP i
s correspondence and reprint requests to Krista A. Goul-
The
D., Department of Orthopaedics, The Ottawa Hospital, withdrawal of the patient’s peripheral blood, fo
h Rd, RM CCW 1637,Use of Platelet-Rich Plasma in Arthroscopy and a concentration of p
The Ottawa, Ontario K1H8L6, Canada. by centrifugation to obtain Sports
ristagoulding@hotmail.com and cytokines well above serum baseline.3 Ho
Medicine: Optimizing the Healing Environment
0 by the Arthroscopy Association of North America
063/10/2602-9539$36.00/0 there are differences between commercial s
1016/j.arthro.2009.11.015 with respect to the preparation protocol, num
Emilio Lopez-Vidriero, M.D., Ph.D., Krista A. Goulding, M.D., David A. Simon, M.D.,
Mikel Sanchez, M.D., and Donald H. Johnson, M.D., F.R.C.S.C.

Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 26, No 2 (February), 2010: pp 269-278
Abstract: Platelet-rich plasma (PRP) is a new technology focused on enhancing the healing response
after injury of different tissue types. PRP is prepared by withdrawal of patients’ peripheral blood and
centrifugation to obtain a highly concentrated sample of platelets, which undergo degranulation to
BOAS INDICAÇÕES PARA ALGUMAS TENDINOPATIAS
release growth factors with healing properties. It also contains plasma, cytokines, thrombin, and other
growth factors that are implicated in wound healing and have inherent biological and adhesive
REVISÕES DE ESTUDOS DE ALTA EVIDÊNCIA CIENTÍFICA
properties. The prepared concentrate is then injected back into the patient at the site of morbidity.
This may be intralesional, intra-articular, or surrounding the involved tissue bed. PRP preparations
have been used therapeutically in various medical fields from implantology to vascular ulcers, with
NECESSIDADES DE MAIS ESTUDOS PARA OUTRAS PATOLOGIAS
a more recent evolution and promising results in the field of sports medicine and arthroscopy. Sports
medicine patients desire a rapid return to their preinjury level of function, and PRP may have certain
applications that will speed recovery in cases of tendon, ligament, muscle, and cartilage disorders. In
(COLUNA, LESÕES ÓSSEAS QUE NÃO CICATRIZAM)
particular, anterior cruciate ligament reconstruction has shown better autograft maturation, improved
donor site morbidity, and pain control, in addition to improved allograft incorporation. By acceler-
ation of the biological integration of the graft by use of PRP, patients may undergo faster, more
intensive rehabilitation programs and return to sports more rapidly. Because of its autogenous origin,
easy preparation, and excellent safety profile, the advent of PRP has opened another therapeutic door

Estudos em animais
Can Platelet-Rich Plasma Enhance Tendon Repair?
Marieke de Mos, Anna E. van der Windt, Holger Jahr, Hans T. M. van
Schie, Harrie Weinans, Jan A. N. Verhaar and Gerjo J. V. M. van Osch
Am J Sports Med 2008 36: 1171
Vol. 36, No. 6, 2008
Vol. 36, No. 6, 2008 Can Platelet-Rich Plasma Enhance Tendon Repair? 1175
Can Platelet-Rich Plasma Enhance Tendon Repair? 1175

50 ** 77

Total collagen (condition/control)
50

Total collagen (condition/control)
DNA content (condition/control)

**
Expressão DNA Colágeno Total **
DNA content (condition/control)

66
**
40
40
5 **
5 **
**
30
30 44
** **
**
33
20
20
22
10 *
10 ** * 11

00
00
T4
T4 T7
T7 T14
T14
T4
T4 T7
T7 T14
T14 days
days
days
days
control
control 10% PPCR
10% PPCR 10% PRCR
10% PRCR
control
control 10% PPCR
10% PPCR 10% PRCR
10% PRCR
20% PPCR
20% PPCR 20% PRCR
20% PRCR
20% PPCR
20% PPCR 20% PRCR
20% PRCR

Figure 2. Deoxyribonucleic acid (DNA) content of tenocyte Figure 3. Total amount of collagen synthesized by tenocytes
Figure 3. Total amount of collagen synthesized by tenocytes
Figure 2. Deoxyribonucleic acid (DNA) content of tenocyte
cultured with or without platelet-rich clot releasate (PRCR) or
cultured with or without platelet-rich clot releasate
cultures with or without platelet-rich clot releasate (PRCR) or Windt AE, Holger Jahr H et al, Am J Sports Med 36:(PRCR) 2008
cultures with or without platelet-rich clot releasate (PRCR) or
De Mos M, Van der 1171-,
or
platelet-poor clot releasate (PPCR). Cells were harvested at platelet-poor clot releasate (PPCR). Collagen was measured
platelet-poor clot releasate (PPCR). Collagen was measured
platelet-poor clot releasate (PPCR). Cells were harvested at
at day 4, 7, and 14. Total amount of collagen for each condi-

2 195 4.17 4050
3 119 3.63 4313
oor plasma (PPP) 1 4.33 0.10 0.00 0.02 ± 0.00
2 5.00 0.10 0.00
3 3.00 0.10 10.00
ch plasma (PRP) 1 451 14.47 2570 2.55 ± 0.16

Expressão Gênica - Tendões
2 488 4.27 1750
3 324 8.90 2437
oor clot releasate (PPCR) 1 6.00 0.10 10.00 0.05 ± 0.02
2 11.00 0.10 10.00
3 8.00 0.10 10.00
ch clot releasate (PRCR) 1 7.00 0.10 10.00 0.08 ± 0.07
2 7.00 0.10 10.00
3 19.00 0.10 90.00

Controle PPP PRP
ESTUDO IN VIVO
3 TENDÕES IT (CIRURGIA)
CULTURA CEL. TEND. 10 DIAS

9 VOLUNTÁRIOS (COL. SANGUE)
PREPARO PRP, PPP, CONTROLE
Conclusion: In human tenocyte cultures,
PRCR, but also PPCR, stimulates cell
proliferation and total collagen production.
PRCR, but not PPCR, slightly increases
the expression of matrix-degrading
enzymes and endogenous growth factors.
Photomicrographs of tenocyte cultures with or without platelet-rich clot releasate (PRCR) or platelet-poor clot releas-
R). Representative photomicrographs (200× magnification) are shown of control, 20% PPCR, and 20% PRCR condi-
days 1, 4, and 14 of the experimental culture period. De Mos M, Van der Windt AE, Holger Jahr H et al, Am J Sports Med 36: 1171-, 2008

Cicatrização - cartilagem
NECESSIDADES PARA O TRATAMENTO IDEAL

1. Bom ambiente

Scafold colágeno

2. Células precursoras

Condroblastos

3. Fatores de crescimento

PDGF, TGF beta, IGF

Caso Clínico - Tênis proﬁssional

23 anos, fem, rk 1 Brasil, rk 150 WTA em 2010

Meniscectomia partial lateral 7 meses atrás

Dor + derrame articular após treinos / jogos

Não voltou a competir depois da artroscopia

EF: derrame articular + dor na face lateral (articular)

RM - Les. condral grau 3-4

Microfratura + PRP (FU 2 anos)

HD - LES. CONDRAL GRAU III / TENISTA AMADOR, 54 ANOS

Evidências Atuais - PRP

Bons / Excelentes resultados

Epicondilite lateral de cotovelo

PRP Vs Inﬁltração com CE (Nível 1 - ECRP)

Tratamento conjunto com Artroplastia de Joelho

Artroplastia Com Vs Sem PRP (Nível 2 - Coorte)

Tendão de Aquiles
PRP para tratamento de tendinopatias com rupturas
parciais / rupturas totais

Objective To examine whether a PRP injection would improve outcome in chronic
midportion Achilles tendinopathy.
Design, Setting, and Patients A stratified, block-randomized, double-blind, placebo-

ACHIL-
Tendinopatia de Aquiles
controlled trial at a single center (The Hague Medical Center, Leidschendam, the Neth-
erlands) of 54 randomized patients aged 18 to 70 years with chronic tendinopathy 2
to 7 cm above the Achilles tendon insertion. The trial was conducted between August
tprob- 28, 2008, and January 29, 2009, with follow-up until July 16, 2009.
sport Resultados insatisfatórios (efeito with either a PRP injection (PRP group)
Intervention Eccentric exercises (usual care)
semelhante ao placebo)
nactive or saline injection (placebo group). Randomization was stratified by activity level.
mated Tendinopatia de Aquiles (semVictorian Institute of1, ECRP)
Main Outcome Measures The validated
ruptura - NE Sports Assessment-
njuries Achilles (VISA-A) questionnaire, which evaluated pain score and activity level, was com-
stance pleted at baseline and 6,pacientes cada) VISA-A score ranged from 0 to 100,
2 grupos (27 12, and 24 weeks. The - somente espessamento
2% for with higher scores corresponding with da pain and increased activity. Treatment group
tendinoso / avaliação less dor somente
endon effects were evaluated using general linear models on the basis of intention-to-treat.
sation Results After randomization into the PRP Salina / Exerc. Excêntrico)
PRP (GPS II, Biomet®) vs group (n=27) or placebo group (n=27),
e with there was complete follow-up of all patients. The mean VISA-A score improved sig-
vative nificantly after 24 weeks in the PRP group by 21.7 points (95% confidence interval
to45% [CI], 13.0-30.5) and in the Platelet-Rich Plasma Injection for Chronic Achilles
placebo group by 20.5 points (95% CI, 11.6-29.4). The
gery.1,5 increase was not significantly different between both groups (adjusted between-
Tendinopathy: A Randomized Controlled Trial
group difference from baseline toJ.24 Vos; Adam Weir; 95% T. M. −12.4 to et al. This CI
Robert de weeks, −0.9; Hans CI, van Schie; 10.6).
d con-
did not of January 15, 2010.
include the predefined relevant difference of 12 points in favor of PRP treat-
Online article and related content
current as JAMA. 2010;303(2):144-149 (doi:10.1001/jama.2009.1986)
ment.
y and http://jama.ama-assn.org/cgi/content/full/303/2/144
Conclusion Among patients with chronic Achilles tendinopathy who were treated
d, but
with eccentric exercises, a PRP injectionarticle is corrected.
Contact me if this compared with a saline injection did not re-
cause- Correction
sult in greater improvementContact me when this article is cited.
in pain and activity.
he no- Citations
Trial Registration clinicaltrials.gov Identifier: NCT00761423
Topic collections Pain; Rehabilitation Medicine; Sports Medicine; Randomized Controlled Trial;

Evidências Atuais
Tendinopatia de Aquiles (Poster AAOS 2010, New Orleans)
30 pacientes / PRP não ativado (Accelerate®, Exatech)
Imobilização por 48 horas / após isso = carga total
Controle do resultado com US/RM
NE 4 (série de casos)
Post- treatment AOFAS scores improved to 84 (80-87), at 1 month, 87 (84-90), at 2 months, 88
(87-100) at 3 months, and 92 (87- 100) at 6 months. Resolution of Achilles abnormalities were seen in
post treatment MRI/ultrasound studies and 28/30 were clinically satisﬁed with their clinical results.

Paper No. 714
Platelet rich Plasma (PRP) effectively Treats Chronic Achilles
Tendonosis
Raymond R Monto, MD, West Tisbury, MA

Tendinopatia com ruptura Figure 1: Sonographic images of the
lesion with vacuum and thick irregular
edges (A), the reparative process (B),
Ruptura parcial - Aquiles (2011) - nível 4 (série de casos)
and final follow-up at 3 months (C).

Figure 2: MRIs of the lesion with disruption of the signal
within the tendon and widening of the tendon edges (A),
the reparative process (B), and final follow-up at 3 months
(C).

Considering the limited blood supply and consequently the difficult and slow repair
Nonoperative Biological Treatment Approach for Partial Achilles
processes of this anatomic region that often requires surgical treatment and several
Tendon Lesion
months for full recovery of functional capacities, we used platelet growth factors
through multiple platelet-rich plasma injections as treatment to improve the tendon
healing potential and favor tissue repair.
By Giuseppe Filardo, MD; Mirco Lo Presti, MD; Elizaveta Kon, MD; Maurilio
Marcacci, MD

Caso clínico

MC, 42 ANOS, TÊNIS AMADOR
RUPTURA - AGUDA

Corredor, masc, 45 anos - Jan 2011

Agosto 2011(7 meses)

Futebol, masc, 47 anos - Outubro 2006 (ruptura completa)

Janeiro 2007
(3 meses)

Tennis elbow
Aplicações da terapia com plasma rico em plaquetas para o
tratamento da tendinopatia lateral crônica do cotovelo

http://ajs.sagepub.com/

Nível Evidência 1 (ECRP)
60

95% CI DASH
95% CIVAS
Positive Effect of an Autologous Platelet Concentrate in Lateral Epicondylitis in a Double-Blind
40
Randomized Controlled Trial: Platelet-Rich Plasma Versus Corticosteroid Injection With a 1-Year
Follow-up
Joost C. Peerbooms, Jordi Sluimer, Daniël J. Bruijn and Taco Gosens
DOI: 10.1177/0363546509355445
Vol. 38, No. 2, 2010 20
The online version of this article can be found at: Sucesso = Dim > 25%
Platelet-rich Plasma Versus Corticosteroid Injection
259
http://ajs.sagepub.com/content/38/2/255

80 200.00 VAS * PRP CE
P < 0.001 Published by:
0
E/B
4 8 12 26 52

150.00 (satisfatórios) FU (months)
http://www.sagepublications.com
73% 49%
60

On behalf of: Time CS PRP
95% CI DASH
95% CIVAS

(wks)
100.00
Average ± SD Average ± SD
40 American Orthopaedic Society for Sports Medicine
VAS 0 65.8 ± 13.8 70.1 ± 15.1
50.00
4 44.2 ± 26.4 55.4 ± 24.2
20
X - PRP 8 42.9 ± 29.2 46.9 ± 24.9
Additional services and information for The American Journal of Sports Medicine can be found at:
O - Corticóide 0.00
12 44.2 ± 27.1 38.7 ± 27.2
0 4 8
Email Alerts: http://ajs.sagepub.com/cgi/alerts 12 26 52
0 4 8 12 26 52 26 FU (months) ± 23.2
56.6 32.6 ± 31.5
FU (months) Subscriptions: http://ajs.sagepub.com/subscriptions Fig
t 52 CS50.1 ± 28.1 PRP 25.3 ± 31.2
(wks) ste
Time CS PRP
(wks) Reprints: http://www.sagepub.com/journalsReprints.nav± SD
Average Average ± SD the

95% CI DASH
Positive Effect of an Autologous Platelet Concentrate in Lateral Epicondylitis in a Double-Blind
Randomized Controlled Trial: Platelet-Rich 100.00 Versus Corticosteroid Injection With a 1-Year
Plasma
Follow-up
Joost C. Peerbooms, Jordi Sluimer, Daniël J. Bruijn and Taco Gosens
DOI: 10.1177/0363546509355445
Platelet-rich Plasma Versus Corticosteroid Injection 259
50.00
The online version of this article can be found at:
http://ajs.sagepub.com/content/38/2/255
200.00
X - PRP
O - Corticóide
P = 0.005
Published by: DASH * PRP CE
0.00
E/B
150.00
http://www.sagepublications.com
0
(satisfatórios) 8
4 73%
12 26 51%
52
4 8 12 26 52 On behalf of: FU (months)
95% CI DASH

FU (months) t CS PRP
100.00 (wks)
American Orthopaedic Society for Sports Medicine
Time CS PRP
(wks) Average ± SD Average ± SD

Average ± SD Average ± SD DASH 0 131.2 ± 58.2 161.3 ± 62.4

50.00 4 97.4 ± 69.0 135.9 ± 78.0
0 65.8 ± Additional services 15.1information for The American Journal of Sports Medicine can be found at:
13.8 70.1 ± and
8 84.7 ± 73.4 113.4 ± 79.6
4 44.2 ± 26.4 55.4 ± 24.2 Email Alerts: http://ajs.sagepub.com/cgi/alerts
12 92.2 ± 68.7 92.0 ± 78.8
8 0.0042.9 ± 29.2 46.9 ± 24.9 Subscriptions: http://ajs.sagepub.com/subscriptions 117.3 ± 75.6
26 79.5 ± 80.3
12 44.2 ± 27.1 38.7 ± 27.2
Reprints: http://www.sagepub.com/journalsReprints.nav 108.4 ± 82.2
52 54.7 ± 73.2
0 4 8 12 26 52
26 56.6 ± 23.2 32.6 ±(months)
FU 31.5
Permissions: http://www.sagepub.com/journalsPermissions.nav
Figure 3. Twenty-five of the 49 patients (51%) in the cortico-
52 50.1 ± 28.1 t 25.3 ± 31.2
CS PRP
steroid (CS) group and 37 of the 51 patients (73%) patients in

Caso Clínico - TE 1 (amador)
FMC, 44 anos, sexo masculino, dor no cotovelo há
8 meses (ﬁsioterapia + OC sem sucesso)

Caso Clínico - TE 1 (amador)
FMC, 44 anos, sexo masculino, dor no cotovelo há
8 meses (ﬁsioterapia + OC sem sucesso)

4 SEMANAS POS PRP
ASSINTOMÁTICO

Lesão Muscular
tratamento das lesões musculares no esporte

Evidências - nível 4
Experiências pessoais, série de casos

Maior parte dos resultados: diminuição do período de
afastamento do esporte (30 a 50%)

Menor incidência de ﬁbrose tecidual

Menor índice de recidiva

Sanchez et al

20 atletas = retorno ao esporte em metade do tempo

Sanchez M, Anitua E, Andia I. Application of autologous growth factors on skeletal muscle healing. Presented at
the Second International Conference on Regenerative Medicine, Leipzig, Germany, May 18-20, 2005

Caso Clínico - Tennis leg
FF, 44 anos, masculino, empresário, atleta amador de tênis

Fisgada perna D durante partida de tênis (há 4 horas)

D D E D E

Ruptura muscular (g.3) gastrocnêmio medial (5 cm)

Aplicação de PRP (24 horas após a lesão)

Inﬁltração única (6ml) na lesão, guiada por US

Retorno ao esporte = 3 semanas (sem dor com 1 semana
pós-aplicação)

Sem recidivas até o momento (2 anos e meio)

US CONTROLE = 4 SEMANAS

Jumper’s Knee
tratamento da tendinopatia do aparelho extensor do joelho

Nível evidência 4 8 ATLETAS
4 MESES FU

Use of platelet-rich plasma for the treatment of refractory
jumper’s knee
NE 4 - Caso Controle
International Orthopaedics (SICOT)
DOI 10.1007/s00264-009-0845-7
surpasses the adaptive abilities of the tendon and causes
micro tears and degeneration in the tendon substance.
ORIGINAL PAPER
Giuseppe Filardo Elizaveta Kon Stefano Della Villa
Many factors have been suspected& predispose patients
to
to this condition [2] by increasing the patellar tendon
otherwise degenerative process, leading to strengthening
of the tendon through the formation of granulation tissue
and tissue regeneration, in a tendon with an increased
& &
healing potential. The effect of autologous blood injections
Ferruccio Vincentelli Pier Maria Fornasari &
overload. The high chronic repetitive loading stimulates the
local release of cytokines, with an autocrine and paracrine
&
into the tendon have been evaluated in vitro and in vivo,
whereby an increase in rabbit patellar tendon strength has
Maurilio Marcacci plasma for the treatment of refractory
Use of platelet-rich
modulation of cell activity [14], that fails to adapt to been assessed [15]. Clinical applications for the treatment

jumper’s knee
continued abusive load and irritation and leads to intra-
tendinous damage. The poor regeneration capacity of
of chronic tendinopathies have also showed good results
[16–19]. International Orthopaedics (SICOT) 15 atletas (PRP 3 aplicações
tendons, explained by the poor vascularity, oxygenation The benefits are the result of some kind of bleeding,
and nutritionFilardo tissue, cannotKon & Stefano applied Villa &
Giuseppe of this & Elizaveta cope with the Della
forces and explains the low healing potential and the
DOI 10.1007/s00264-009-0845-7
which stimulates the healing response through chemical
modifiers of cellular activity contained in the blood. In
a cada 2 semanas)
Ferruccio Vincentelli & Pier Maria Fornasari &
difficulties in the treatment of this chronic tendon disease cases of injury, platelets are PAPER
ORIGINAL the first cells carried to the
Maurilio Marcacci
[14]. lesion site and, in fact, they play a key role in mediating
Recently, some authors [15, 16] have postulated that healing of the damaged tissue because of the capacity to
Received: 21 June 2009 / Revised: 12 July 2009 / Accepted: 13 July 2009
autologous blood injections might provide the necessary release growth factors from their α-granules [20]. Platelets
Controle: 16 pacientes (ﬁsio)
# Springer-Verlag 2009
cellular and humoral mediators to induce the healing contain storage pools of growth factors including PDGF,

Use of platelet-rich plasma for the treatment of re
cascade and promote tendon repair. The rationale was TGF-β, VEGF, IGF-1, FGF, and cytokines, chemokines
Received: 21 June 2009 / Revised: 12 July 2009 / Accepted: 13 July 2009
based on the mitomorphogenic activity of blood growth
# Springer-Verlag 2009 and metabolites [20]. Platelet-rich plasma is a concentrate
factors and the inflammatory response induced in an of platelets and therefore autologous growth factors.

The aim of this study was to evaluate the knee
jumper’s efficacy proach.A statistically injections were perf
signiﬁcant
Abstract
Fig. 4 A 22-year-old soccer
Abstract The aim of this study was to evaluate the efficacy
Multiple PRP
proach. Multiple PRP injections were performed on three
player with a three year history
of multiple platelet-rich plasma (PRP) injections apart into the site of patellar two weeks apart into the s
occasions two weeks on the
of refractory jumper’s knee who plasma (PRP) injections on the
of multiple platelet-rich improvement in all scores was
occasions
failed both non-operative treat- tendinopathy. Filardo & Elizaveta Kon & Stefano Della Villa &
Giuseppe Tegner, EQ VAS and pain level were used
healing of chronic refractory patellar tendinopathy after
ments and surgery. The patient
for tendinopathy at the end oftendinopathy. Tegner,end of the and pain
healing of chronic refractory patellar clinical evaluation before,&after Mariathe treatment &
previous classical treatments have failed. We treated 15
returned to previous activity Ferruccio Vincentelli Pier observed at the EQ VAS PRP
Fornasari
level after four months;by chronic jumper’s knee, who had failed
patients affected MRI and at six months follow-up. Complications, functional
previous classical treatments have failed. andMarcacci
shows the patellar tendon before
recovery We treated 15 for clinical evaluation before, at the end o
Maurilio patient satisfaction were also recorded. A
previous nonsurgical or surgical treatments, with multiple
treatment (a) and the improve- injections in patients with chronic
patients affected by chronic jumper’sobserved at the end of the PRP injections inand with
statistically who had failed in all scoresat six months follow-up. Complicat
ment of injections and physiotherapy. We also compared the
PRP the tendon structure knee,
after the platelet-rich plasma a homogeneous group of 16 patients
clinical outcome with
significant improvement
patients
was

chronic refractory patellar tendinopathy and arefractory patient satisfaction were al
previous nonsurgical or surgical treatments, with multiple recovery and patellar tendinopathy
(PRP) injections at six months’
follow-up (b) treated exclusively with the physiotherapy ap-
primarily further
improvement was noted at six months, after physiotherapy
was also Moreover, comparable 12 July 2009 / Accepted: 13 July improvement was in
PRP injections and physiotherapy. We added. 21compared theresults were obtaineda further 2009
Received: June 2009 / Revised:
statistically significant improvement
and
G. Filardo : E. Kon : M. Marcacci
clinical Orthopedic and Sports Trauma, homogeneous group toevaluation, as in cases to recover and patient at the end of the PRP injections
Department of outcome with a
# respect of 16 severe
withSpringer-Verlag 2009
the less
observed
patientsin the EQ VAS score
Biomechanics Laboratory, Rizzoli Orthopaedic Institute,
and pain level time noted at six months, after
primarily treated exclusively with the physiotherapy ap-
Bologna, Italy satisfaction, with an even higher improvement in the sport refractory patellar tendinopathy
chronic
activity level achieved in the PRP group. The clinical
E. Kon
e-mail: e.kon@biomec.ior.it
physiotherapy was Multiple PRP afte
improvement was
results are encouraging, indicating that PRP injections have
proach. added
Abstract The aim of this study was to evaluate the efficacy noted at six months, inject
of multiple platelet-rich plasma (PRP) injections on the occasions two weeks apa
M. Marcacci was chronic
added. Moreover, comparable results
the potential to promote the achievement of a satisfactory
clinical outcome, even in difficult cases with tendinopathy after
healing of chronic refractory patellar tendinopathy. Tegner, EQ V
e-mail: m.marcacci@biomec.ior.it:
: E. Kon M. Marcacci
G. Filardo refractory tendinopathy after previous classicalfailed. We treated the less severe evaluation befor
previous classical treatments have treatmentswith respect to 15 for clinical cases in the

Caso Clínico - Jumper’s Knee
VC, Tenista amador, 41 anos, 1 ano e meio de dor no tendão patelar D

Realizou 45 sessões de ﬁsio, sem melhora (por 4 meses)

* Aplicação - Longitudinal * Aplicação - Axial

Caso Clínico - Jumper’s Knee
Paciente sem dor
3a. sem

* 4sem US Controle * 4sem US Controle (Axial)

Lesões do LCA
tratamento das lesões do LCA do joelho

Estudos experimentais
Collagen-Platelet Composites Improve the Biomechanical Properties of Healing
Anterior Cruciate Ligament Grafts in a Porcine Model
Braden C. Fleming, Kurt P. Spindler, Matthew P. Palmer, Elise M. Magarian and Martha M.
Murray
Winner of the 2009 Cabaud Award
Collagen-Platelet Composites Improve
Article Title
Conclusion: Properties of Healing
13 joelhos / porco / Aloenxerto Biomechanical These data demonstrate that
the Subtitle
Vol. 37, No. 8, 2009 Article Platelets Enhance Porcine ACL Graft Healing 1555

Anterior Cruciate Ligament at the time of ACL
Author the application of CPC Grafts in
Affiliation
a Porcine Model
reconstruction improves the structural
properties of the graft and reduces early
Braden C.goes here andPhD, Kurtcolumns. † ‡
The abstract Fleming,* covers two P. Spindler, MD, Matthew P. Palmer, Elise M. Magarian,
Martha M. Murray, MD
‡§
andabstract goes here and covers two columns.
‡

The
From the *Department of Orthopaedics, Warren Alpert Medical School, Brown University,
AP knee laxity in the porcine model after
The abstract goes here and covers two columns.
†
Providence, Rhode Island, the Department of Orthopaedics and Rehabilitation, Vanderbilt
The abstract goes here and covers two columns.
Sports Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, and the
‡ 15 weeks of healing.
Department of Orthopaedic Surgery, Children’s Hospital Boston, Boston, Massachusetts
KEY WORDS list of key words goes here

Clinical Relevance: Application of a CPC
Background: The outcome of anterior cruciate ligament (ACL) reconstruction is variable, and many patients have increased joint
laxity postoperatively.
to an ACL graft at the time of surgery
Hypothesis: Placement of a collagen-platelet composite (CPC) around the graft at the time of ACL reconstruction decreases
postoperative knee laxity and improves the structural properties of the graft compared with standard ACL reconstruction.
decreased knee laxity and increased the
Study Design: Controlled laboratory study.
Methods: Thirteen immature pigs underwent unilateral ACL reconstruction with a bone–patellar tendon–bone allograft. In 6 pigs,
a standard allograft was used to reconstruct the ACL. In 7 pigs, a CPC was placed aroundgraft after 15 heal-
structural properties of the the allograft. After 15 weeks of
ing, the animals were euthanized, and the anterior-posterior (AP) knee laxity and structural properties of the graft were measured.

weeks of healing.
Qualitative histology of the grafts was also performed.
Figure 1. Schematic of standard anterior cruciate ligament (ACL) reconstruction (ACLR) (top) and enhanced ACL reconstruction
Results: The AP laxity values of the reconstructed knees, normalized to the contralateral control, were significantly reduced by
with the collagen-platelet composite (CPC) (E-ACLR) (bottom) is shown. A collagen sleeve was threaded over the graft and infil-
trated with autologous 5X platelet-rich plasma to form the CPC. 28% and 57% at 60° and 90° of knee flexion, respectively, with the addition of CPC (P .001). Significant improvements in the

To maximize the platelet concentration, we pipetted All ACL reconstructions were performed by the same
out material into a fresh sterile Vacurette without surgical team, using the same anesthetic technique, that
citrate around the dividing line (buffy coat) between is, general anesthesia with a laryngeal mask and with
these 2 phases. This pipetted material is again centri- tourniquet ischemia of 300 mm Hg. We started arthros-
fuged for 6 minutes at 1,000 rpm (380g) at room copy repairing associated lesions, and afterward, we re-
temperature. After the second centrifugation, we ob- constructed the ACL with patellar tendon allograft with

Estudo clínico NE1 (ECRP)
tained 2 levels. The top fraction is yellow serum with a RigidFix technique (DePuy Mitek, Raynham, MA)19
fibrinogen and has a very low concentration of plate- with 2 biodegradable cross pins to fixate the femoral
J. R. VALENTÍ NIN ET AL. lets (platelet-poor plasma). The remaining substance bone and a tibial biodegradable interference screw.
is the available platelet concentrate, rich in platelets Partial meniscectomy was performed when the me-
with autologous fibrinogen. niscal lesions were irreparable; these included degen-
m component and blood cell component Surgical Technique erated or radial tears. All meniscal repairs were per-
We obtain one pipette with platelet-rich plasma and
concentration of platelets. formed for fresh lesions and those involving the
other with platelet-poor plasma. The whole process
All ACL reconstructions were performed by the same
e the platelet concentration, we pipetted vascular region with all-inside methods. The Smith &
nto a fresh sterile Vacurette without surgical team, using the samelasts 45 minutes. Thereafter, in the operating room we
anesthetic technique, that
Has Platelet-Rich Plasma Any Role in Anterior Cruciate Ligament Allograft Healing?
the dividing line (buffy coat) between is, general anesthesia with a laryngeal mask chloride
add 10% calcium and with(0.05 mL of calcium chlo-
ride for each milliliter of platelet-rich plasma) to ac-
Nephew FasT-Fix Meniscal Repair System (Smith &
Nephew Endoscopy, Andover, MA) was the only all-
This pipetted material is again centri- tourniquet ischemia of 300 mm Hg. We started arthros- inside suture used. No inside-out methods were used.
tivate platelets to release their growth factors. Within
Juan Ramón Valentí Nin, M.D., Ph.D., Gonzalo Mora Gasque, M.D., Ph.D., Andrés Valentí Azcárate, M.D.,
minutes at 1,000 rpm (380g) at room copy repairing associated lesions, and afterward, we re- the coagulum has solidi-
approximately 15 minutes, In the gel group the ligament was covered with gel
fter the second centrifugation, we ob- constructed the ACL with patellarand the gel is obtained (Fig 1A).
fied tendon allograft with and sutured over itself with gel in its interior (Fig 1B).
Jesús Dámaso aAquerreta Beola, M.D.,Raynham, MA) Milagros Hernandez Gonzalez, M.D., Ph.D.
The top fraction is yellow serum with RigidFix technique (DePuy Mitek, Ph.D., and 19

has a very low concentration of plate- with 2 biodegradable cross pins to fixate the femoral
oor plasma). The remaining substance
e platelet concentrate, rich in platelets
Arthroscopy 25(11) 2009: pp 1206-1213
bone and a tibial biodegradable interference screw.
Partial meniscectomy was performed when the me-
s fibrinogen. niscal lesions were irreparable; these included degen-
ne pipette with platelet-rich plasma and erated or radial tears. All meniscal repairs were per-
telet-poor plasma. The whole process formed for fresh lesions and those involving the
100 pacientes - 2 grupos 50 / rLCA TP com e sem PRP (manual)
s. Thereafter, in the operating room we vascular region with all-inside methods. The Smith &
um chloride (0.05 mL of calcium chlo- Nephew FasT-Fix Meniscal Repair System (Smith &
24 meses avaliação (IKDC, RX e RM, VAS)
milliliter of platelet-rich plasma) to ac-
to release their growth factors. Within
Nephew Endoscopy, Andover, MA) was the only all-
inside suture used. No inside-out methods were used.
PRP no enxerto (sem sutura) e no túnel tibial
15 minutes, the coagulum has solidi-
l is obtained (Fig 1A).
In the gel group the ligament was covered with gel
and sutured over itself with gel in its interior (Fig 1B).
FIGURE 1. (A) Gel activated
after addition of 10% calcium
chloride. (B) Gel introduced
into ligament. (C) Gel placed in
tibial tunnel. (D) Intra-articular
view of allograft with gel.

Gel activated
10% calcium
l introduced
Gel placed in
ntra-articular
with gel.

Estudo clínico NE1 (ECRP)
Has Platelet-Rich Plasma Any Role in Anterior Cruciate Ligament Allograft Healing?
Juan Ramón Valentí Nin, M.D., Ph.D., Gonzalo Mora Gasque, M.D., Ph.D., Andrés Valentí Azcárate, M.D.,
Jesús Dámaso Aquerreta Beola, M.D., Ph.D., and Milagros Hernandez Gonzalez, M.D., Ph.D.
Arthroscopy 25(11) 2009: pp 1206-1213

Conclusions: At this time, the therapeutic role of PDGF in ACL
reconstruction remains unclear. The use of PDGF, on the graft and inside the
tibial tunnel, in patients treated with bone–patellar tendon–bone allografts
has no discernable clinical or biomechanical effect at 2 years’ follow-up.
More clinical studies will be needed to show the efﬁcacy and use of these
factors in daily practice in ACL reconstruction.

made, and the tendon’s thickness and length are mea-
sured. Under moderate tension, a piece of Gelfoam is
placed between the portion of the tendons that will be
located in the femoral tunnel and the intra-articular FIGURE 2. The Gelfoam acts as a sponge that main

Estudo clínico NE3 (caso-controle)
segment. This is sutured to the adjacent tendon with dose in direct contact with the graft.
No. 3-0 Vicryl. The Gelfoam acts as a sponge that
maintains the platelet concentrate dose in direct con-
tact with the graft used (Fig 1). A total volume of 5 ACL GRAFT AN
Imaging Assessment
mL of platelet-rich plasma, activated at the moment of
inoculation on the graft, is added homogeneously so The imaging protocol was standardized
Comparison of Magnetic Resonance Imaging Findings in Anterior Cruciate
as to completely cover the graft, waiting until it forms
a clot (Fig 2). The dose administered was determined
in both groups. Included were a series o
focused to study the intra-articular seg
Ligament Grafts With and Without Autologous Platelet-Derived Growth Factors
based only on our criteria. We do not know the ideal graft. The study of the femoral and tibial
Fernando Radice, Roberto Yánez, Vicente thebeen published. Thenothing about ad-
dose, and at
ideal dose had
time of this study,
Gutiérrez, Julio Rosales, Miguel
formed clot
the
Pinedo,notﬁrst, compared with its ma
graft was
cess occurs
considered because
Sebastián Coda the in
Arthroscopy 26(1):2010: pp 50-57
heres to the graft, because of the presence of the part. This was performed with a T1 and
sutured and compressed Gelfoam. This allows the (repetition time, 4,020 milliseconds; ech
graft to hold a precise amount of PRPG and, even milliseconds) with a 1.5-T Siemens Mag
Scanner (Siemens AG, Erlangen, German
50 pacientes - PRP vs Controle
more importantly, avoids the loss of PRPG when the
graft goes through the bone tunnels (Fig 3). 2 mm in thickness, in the oblique paras
between 10° and 15°, centered on the i
ET AL. RecLCA STGC e TP / gelfoam® + PRP (GPSII®, Biomet) region, with the knee ﬂexed at 9° to
obtained. Patients in group A had MRI per
4, 5, 6, 7, 8, and 9 months postoperativ
build a homogenization curve of the graf
to the statistic quadratic predictive mod
ported by this study’s hypothesis that the u
accelerates the graft homogenization time
group had MRI performed at 6, 7, 8, 9, 10
months, with the assumption that befor
homogenization is not present.
The imaging analysis was done by t
diologist, experienced in musculoskele
blinded to the time of reconstruction an
application to the graft.
The radiologist divided the intra-articu
of the graft into 3 segments: proximal,
distal. To each segment, he assigned a sco
to the degree of heterogeneity observed.
FIGURE 2. The Gelfoam acts as a sponge that maintains the PRPG IGURE 1. Hamstring graft preparation with Gelfoam and PRPG.
F score of 0 was assigned to an absolutely h

54 F. RADICE ET AL.

D AUTOLOGOUS PDGF 53
Statistic Analysis
For the statistic analysis, data were analyzed with
the SPSS data analysis program (SPSS, Chicago, IL).
This program was used to work with quadratic
statistics, graphs, data, and descriptive indicators. To
determine whether the 2 groups were comparable in
Comparison of Magnetic Resonance Imaging Findings in Anterior Cruciate terms of number, age, and sex, an F test and Student
t test were used.
Ligament Grafts With and Without Autologous Platelet-Derived Growth Factors The quadratic predictive model was used for data
analysis to determine, through a linear relation, the
extrapolated midpoint that predicted the time when
Fernando Radice, Roberto Yánez, Vicente Gutiérrez, Julio Rosales, Miguel Pinedo, Sebastián Coda both groups had completely homogeneous grafts.

Arthroscopy 26(1):2010: pp 50-57
RESULTS
The mean heterogeneity score value at the time of
MRI, assigned by the radiologist, was 1.14 in group A
and 3.25 in group B. Both groups were comparable in
TP com PRP TP sem PRP terms of sex and age (P Ͻ .05). The mean time to
obtain a completely homogeneous intra-articular seg-
ment in group A (PRPG added) was 177 days after
Conclusions: ACL reconstruction with
surgery, and it was 369 days in group B. Using the
quadratic predictive model, the percentage of time that
group A (PRPG added) needed to achieve the same
the use of PRPG achieves complete
MRI aspect as group B was 48% (Fig 6). This fact is
even more evident when we compared only the BPTB
homogeneous grafts assessed by MRI,
graft cases in both groups: a homogeneous graft was
obtained in 109 days in patients with PRPG versus
363 days in the control group, that is, one third the
in 179 days compared with 369 days
time as that for control group (Fig 7). In the compar-
ative analysis of those patients in whom BPTB graft
for ACL reconstruction without PRPG.
was used, we observed an even shorter time required
for the graft’s homogenization when PRPG was used,

This represents a time shortening of
48% with respect to ACL
ft
he
n-
reconstruction without PRPG.
a-

r-
5 meses
FIGURE 4. (A) MRI 6 months after ACL reconstruction: Ham- 6 meses
FIGURE 5. (A) MRI 6 months after ACL reconstruction: Ham-
string graft with PRPG. A score of 0 was assigned to an absolutely graft without PRPG. A score of 3 was assigned to a severely
string
homogeneous segment. (B) MRI 5 months after ACL reconstruc-
us tion: BPTB graft with PRPG. A score of 0 was assigned to an
heterogeneous segment. (B) MRI 6 months after ACL reconstruc-

Estudo clínico NE3 (caso-controle) ARTICLE IN PRESS
6 M. SÁNCHEZ ET AL.

Ligamentization of Tendon Grafts Treated With an Endogenous Preparation Rich in
Growth Factors: Gross Morphology and Histology
Mikel Sánchez, M.D., Eduardo Anitua, M.D., Juan Azofra, M.D., Roberto Prado, Ph.D., Francisco Muruzabal,
Ph.D., and Isabel Andia, Ph.D.
Arthroscopy 26:2010: preview
ARTICLE IN PRESS
37 pacientes - PRP vs Controle
RecLCA STGC / proc. manual PRP / Second Look
M. SÁNCHEZ ET AL.

Cirurgia 18 meses 16 meses
FIGURE 2. Gross morphology and histology of hamstring tendon grafts (A, B) at
of surgery, the microstructure of the tendon graft shows a uniform aspect of strong
cells (arrowheads). The intrasynovial transformation (C, D) at 18 months (untreated

ies and/or chondral lesions, and removal of metal biolog
staples was necessary in three PRGF-treated patients.Those
One patient in each group presented with plica syn- had m
drome. with c
to 15.

6
ARTICLE IN PRESS
ARTICLE IN PRESS
M. SÁNCHEZ ET AL.
Arthroscopic Evaluations
The mean period from ACL surgery to second-look
arthroscopy and histologic analysis was 15 months
points
As
ture o
6 M. SÁNCHEZ ET AL. that h
(SD, 6), with a range of 6 to 25 months; this interval month
Ligamentization of Tendon Grafts Treated With was an Endogenous Preparation Rich in
similar in the PRGF group (14 Ϯ 6 months) and
linear
control group (17 Ϯ 5 months). Arthroscopic assess-
Growth Factors: Gross Morphologyshown in Table 1. The overall evaluation of ments are and Histology
morph
from
Mikel Sánchez, M.D., Eduardo Anitua, M.D., Juan Azofra, M.D., Roberto Prado, Ph.D., Francisco rating in PRGF-treated grafts showed an excellent Muruzabal,
57.1% of knees and a fair rating in 42.9%. Untreated presen
Ph.D., and Isabel Andia, Ph.D. uous
Arthroscopy 26:2010: preview tween
treate
TABLE 1. Arthroscopic Evaluation of PRGF-Treated and were
Untreated Tendon Grafts contro
% of Grafts (n) Ne
served
Arthroscopic Evaluation Control PRGF
18m most
Synovium coverage contra
Completely covered 33.3 (5) 61.9 (13) the un
Partially covered 46.7 (7) 38.1 (8) conne
Almost not covered 20.0 (3) —
Thickness and apparent tension
surge
No elongation or laceration 40.0 (6) 71.4 (15) after
Partial laceration of thick graft or no come
laceration of thin graft 53.3 (8) 28.6 (6) treate
Complete tear or obvious elongation 6.7 (1) —
Overall evaluation
Pears
Pϭ
16m Excellent
Fair
33.3 (5)
46.7 (7)
57.1 (12)
42.9 (9) the co
Poor 20.0 (3) — Pearso
NOTE. We could not ascertain any signiﬁcant difference be- marke
F 2. Gross morphology and histology of hamstring tendon grafts (A, B) at surgery and (C-F) after ligamentization. (B) At the timetween the 2 groups, Mann-Whitney P ϭ .051.
IGURE and c
of surgery, the microstructure of the tendon graft shows a uniform aspect of strongly oriented collagenous matrix with interspersed spindle
FIGURE 2. Gross morphology and histology of hamstring tendonmonths(A, B) at surgery and (E, F) at 16 ligamentization. (B) At graft) can
cells (arrowheads). The intrasynovial transformation (C, D) at 18 grafts (untreated graft) and (C-F) after months (PRGF-treated the time
of surgery, theThe microstructure the the untreated showsis not uniform andof strongly oriented collagenous matrixremodeling graft (asterisk)
be observed. microstructure of of tendon graft graft a uniform aspect shows 2 well-differentiated areas: the with interspersed spindle

Ligamentization of Tendon Grafts Treated With an Endogenous Preparation Rich in
Growth Factors: Gross Morphology and Histology
Mikel Sánchez, M.D., Eduardo Anitua, M.D., Juan Azofra, M.D., Roberto Prado, Ph.D., Francisco Muruzabal,
Ph.D., and Isabel Andia, Ph.D.
Arthroscopy 26:2010: preview

Conclusions: The use of PRGF inﬂuenced the histologic
characteristics of tendon grafts, resulting in more remodeling
compared with untreated grafts. We have shown temporal
histologic changes during the 6- to 24-month postoperative
period of graft maturation, with newly formed connective tissue
enveloping most grafts treated with PRGF

Osteoartrose
tratamento adjuvante da dor na OA de joelho

Clin Exp Rheumatol. 2009 Mar-Apr;27(2):201-7.
Intraarticular administration of platelet-rich plasma with biodegradable gelatin
hydrogel microspheres prevents osteoarthritis progression in the rabbit knee.
Saito M, Takahashi KA, Arai Y, Inoue A, Sakao K, Tonomura H, Honjo K, Nakagawa S, Inoue H,
Tabata Y, Kubo T.
CONCLUSION: The present findings indicate that sustained release of growth
factors contained in PRP has preventive effects against OA progression. These
preventive effects appear to be due to stimulation of cartilage matrix metabolism,
caused by the growth factors contained in PRP
Rheumatology 2007;46:1769–1772 doi:10.1093/rheumatology/kem234
Advance Access publication 17 October 2007

Concise Report

Platelet-released growth factors enhance the secretion of hyaluronic
acid and induce hepatocyte growth factor production by synovial
fibroblasts from arthritic patients
E. Anitua1, M. Sanchez2, A. T. Nurden3, M. M. Zalduendo1, M. de la Fuente1, J. Azofra2 and I. Andı´ a1
´

Objectives. Autologous platelet-secreted growth factors (GFs) may have therapeutic effects in osteoarthritis (OA) capsular joints via multiple

NOVEL THERAPEUTIC STRATEGIES
Biodrugs 2007; 21 (
1173-8804/07/0005-032

© 2007 Adis Data Information BV. All righ

Autologous Conditioned Serum in the
Treatment of Orthopedic Diseases
The Orthokine® Therapy Biodrugs 2007; 21 (5): 323-332

Peter Wehling,1,2 Carsten Moser,2,3 David Frisbie,4 C. Wayne McIlwraith,4 Christopher E. Kawcak,4
Ruediger Krauspe3 and Julio A. Reinecke5
1 ¨
Centre for Molecular Orthopaedics, Dusseldorf, Germany
2 ¨
Orthogen AG, Dusseldorf, Germany
3 ¨ ¨
Department of Orthopaedics, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany
4 Artigo de revisão sobre ACS
Department of Clinical Sciences, Equine Orthopedic Research Center, College of Veterinary Medicine and Biomedical
Sciences, Colorado State University, Fort Collins, Colorado, USA
5 ¨
Orthogen Veterinary GmbH, Dusseldorf, Germany
Patologias revisadas:
Contents
1. Lesão muscular (estudo piloto em humanos)
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Biologic Mechanisms and Targets in Orthopedic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. ACS e Osteoartrite de joelho
2. Production of Autologous Conditioned Serum (ACS) Utilizing Orthokine® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. ACS in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1 Controlled Equine Osteoarthritis Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Ciática e dor lombar
3.2 Treatment of Muscle Injuries by Local Administration of Conditioned Serum in Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3 Experimental Mouse Muscle Contusion Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. ACS in Clinical Human Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Pilot Observation in Muscle Regeneration for Human Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Randomized Controlled Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Knee Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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