Lars Engebretsen MD, PhD Professor and Chair Department of Orthopaedic Surgery, U of Oslo

PRP in muscle and tendon injuries Lars Engebretsen MD, PhD Professor and Chair Department of Orthopaedic Surgery, U of Oslo

n  Consultant n  Arthrex equipment development

n  Fellowship grants n  Smith and Nephew n  Arthrex

n  Editor and Editorial board n  BJSM n  JBJS (am) n  SJMSS n  KSSTA

Disclosures 2013

n  Research grants n  Smith & Nephew n  Fin-Ceramica n  TBF-Tissue Engineering n  Biomet

n  Competitive grants n  Norwegian NIH n  AOSSM n  FIFA n  IOC n  NIH n  Health South East Norway n  Department of Culture

Norway

n  Cochair of the Oslo Sports Trauma Research Center

n  Chief of the Orthopedic Department at the University of Oslo

n  Consultant at the Norwegian Olympic Center

n  Head of three research groups in Cartilage, Knee ligaments and Injury Prevention

n  Head of Scientific activities in the IOC

n  Past President of ESSKA

n  Editor of BJSM IPHP n  Deputy Editor JBJS (Am)

Been in Sports Traumatology as a clinician researcher since 1984

This lecture will discuss: n  Why is PRP hot? n  Proof of concept?

n  Role in tendon, ligament, muscle and cartilage

n  Procedure- dose- frequency n  White cells ? n  Local anesthesia ? n  Antiinflammatories ? n  Adverse effects ? n  Anti doping regulations n  Summary

IOC Consensus statements

Sports Nutrition (2003) •  Sex Reassignment in Sports (2003) •  Sudden Cardiovascular Death in Sports (2004) •  Training the Elite Child Athlete (2005) •  Female Athlete Triad (2005) •  Sexual Harassment & Abuse in Sport (2006) •  Molecular Basis of Connective Tissue and Muscle Injuries in Sport (2007) •  Non-contact ACL Injury in the Female Athlete (2008) •  Concussion in Sport (2008) •  Asthma in Elite Athletes (2008) •  Fasting in Sports (2009) •  Periodic Health Evaluation of Elite Athletes (2009) •  Age Determination in High-Level Young Athletes (2009) •  Sports Nutrition (2010) •  Functional Hyper-Androgenism and Sport (2010) •  The Use of Platelet-Rich Plasma in Sports Medicine (2010) •  Fitness and Health in Young People through Physical Activity and Sport (2011) •  Thermoregulatory and altitude challenges in the high-level athlete (2011)

Did PRP win it?

n  Hines Ward n  Pittsburgh Steelers

wide receiver n  Super Bowl XLIII Feb

2009 n  Pittsburgh Steelers

versus Ravens

Sandeep Patel MD AJSM 2013

PRP: what does it contain?

Comparison of mean cell counts amongMajor commercial PRP systems

Not all PRPs are the same

n  Leukocytes (white blood cells) n  Platelet concentration

n  Platelet activation

Andia et al. Expert Opin Biol Ther. 2010 Oct;10(10):1415-26

Jia et al. Oper Tech Sports Med. 2011

Differences in PRP Systems Competitor 1 Competitor 2 PRGFTM

Types of PRP L-PRP1 P-PRP2 P-PRP

Input Blood Volume 30-55ml3 9ml4 Variable (9ml per

tube)

Centrifuge Protocol

3200rpm (1100g) for

15min1

1500rpm (400g) for

5min2 580g for 8min

PRP Yield 3-6ml3 2-3ml4 2ml of F2 per tube

Platelet Enrichment

Factor 2.07 ± 1.11 1.3x2 2.3 ± 0.6

Leukocyte Concentration

[103/ul] 34.4 ± 13.61 0.68 ± 0.422 0.7±0.7

Is Scaffold Forming Activator

Included in the Kit?

No No Yes 1Castillo et al. Am J Sports Med. 2011 Feb; 39(2): 266-71

2Sundman et al. Am J Sports Med. 2011 Oct;39(10):2135-40 3 Data available at: http://www.biomet.com/biologics/information/pdf/BBI0003.0.pdf

4 Data Available at: https://www.arthrex.com/innovations/index.cfm?adid=28

Why should it work?

AUTOLOGOUS PLATELETS CAN BE A SOURCE OF GROWTH FACTORS FOR HEALING AND TISSUE REGENERATION

Platelet-Rich Plasma is the outcome of a

centrifugation of autologous blood.

Contains a high concentration of

platelets

(4-8 times)

PLATELETS

Role in HAEMOSTASIS

Growth Factors RELEASE

Ø  Promote tissue repair Ø  Influence the reactivity of vascular and other

blood cells in angiogenesis and inflammation

Where are the GFs?

Platelet activation

§  Activation §  exposed collagen, damage or thrombin §  Dramatic morphological change §  Adhesion, spreading, aggregation,

activation of other platelets and clot retraction

§  Alpha Granule release §  200-500 nm, ~50 to 80 per platelet §  Over 30 bioactive proteins, with

roles in haemostasis and tissue healing.

0.5 µm

Harrison and Cramer 1993

Platelet granule release

Alpha granules migrate to platelet periphery (a), where the plasma membrane blebs (b), and ruptures (c) Loss of electron density with rupture

Polasek J. Lysosomal concept of platelet secretion - revisited. Eur J Haematol 1989. Suppl 50; Vol 43.

SOURCES ROLE PRP (multiplication factor)

Platelets Blood Initial control of haemorrhage, release GF 3-8

PDGF Platelets Stimulates cell replication, angiogenesis, mitogen for fibroblasts 5-29

VEGF Platelets Angiogenesis 6-52,7

TGF-β Platelets Increase chondrocyte expression, induce Chondrogenic differentiation of MSCS, enhance matrix deposition, decrease the suppressive effects of inflammatory mediators IL-1 on proteglycans synthesis in cartilage

3,5-27

FGF Platelets Stimulates proliferation of myoblasts, angiogenesis Detected

EGF Platelets Proliferation of mesencymal and epithelial cells, Potentiation other GF 3

HGF Plasma Angiogenesis, mitogen for endothelial cells, anti-fibrotic No increase from baseline

IGF-1 Plasma Stimultes myoblasts and fibroblasts, mediator in growth and repair of skeletal muscle

No increase from baseline

EGF: epidermal growth factors, HGF: hepatocyte growth factor, IGF-1: insuline-like growth factor, PDGF: platelet-derived growth factor, TGF-b: transforming growth factor beta, VEGF: vascular endothelial growth factor, FGF: fibroblasts growth factor

Mazzocca et al UCon

Does ACP/PRP increase human tendon, bone, cartilage and muscle cell proliferation

Mazzocca et al UCon

Local anesthesia and cortison has a harmfull effect on proliferation of tenocytes

Mazzocca et al U Con

Does repeated dosage help?

Where and when is the action?

n  Cook and Purdam BJSM 2009

n  Reactive tendinopathy?

n  Tendon dysrepair? n  Degenerative

tendinopathy?

Consider a patient with

Achilles tendon pain as just one

example

The heel drop stimulates

integrins to flip and this triggers signaling pathways and PRP

acts??????

The heel drop stimulates

integrins to flip and this triggers signaling pathways

The heel drop stimulates

integrins to flip and this triggers signaling pathways

The heel drop stimulates

integrins to flip and this triggers signaling pathways

The heel drop stimulates integrins to flip and this triggers

signaling pathways

The heel drop stimulates integrins to flip and this triggers

signaling pathways

The nucleus is signaled to

create mRNA and PRP acts?

The nucleus is signaled to

create mRNA

The nucleus is signaled to create mRNA

Gene transcription and PRP acts?

The nucleus is signaled to create mRNA

The nucleus is signaled to create mRNA

The nucleus is signaled to create mRNA

Ribosomes create protein

Ribosomes

Ribosomes create protein

Ribosomes

Collagen extrudes from matrix

Ribosomes

Collagen extrudes from matrix

Collagen is repaired

Recent studies:

Recent RCT in OA:

Knee OA:

RMN AT 6 M F U RMN BASAL

CASE: PATELLAR TENDON LESION

Male, 25 y, D LEAGUE SOCCER PLAYER 3y of pain and limited function, bilateral, previous surgery

RETURNED AT PREVIOUS ACTIVITY LEVEL AT 4 MONTHS

PRP IN TENDON PATOLOGY TREATMENT

ü  PROMISSING RESULTS IN ATHLETES ü  TREATMENT OF FAILED CASES ü  HAVE TO BE COMBINED WITH

PHYSICAL THERAPY ü  RANDOMIZED STUDIES ARE NEEDED

Tendinopathy: Effect?

PRP and muscles

ü  Restricted activity for 24 hours

ü  No use of non-steroidal medication.

ü  Mild activities with bike or mild exercises in pool

AFTER TREATMENT

Use ultrasound guided injections!

This lecture will teach you: n  Why is PRP hot? n  Proof of concept?

n  Role in tendon, ligament, muscle and cartilage

n  Procedure- dose- frequency n  White cells ? n  Local anesthesia ? n  Antiinflammatories ? n  Adverse effects ? n  Anti doping regulations n  Summary

Adverse effects?

n  So far no serious side effects reported

n  A case report on DVT in November 2010 and a comment on being aware of this possibility

This lecture will teach you: n  Why is PRP hot? n  Proof of concept?

n  Role in tendon, ligament, muscle and cartilage

n  Procedure- dose- frequency n  White cells ? n  Local anesthesia ? n  Antiinflammatories ? n  Adverse effects ? n  Anti doping regulations n  Summary

PRP from a regulatory viewpoint:

n  Autologous blood n  No agreement on procurement (degree of

centrifugation, white cells?) n  Principally no difference in mechanism on

muscle, tendon and ligaments n  No indication that PRP has any effect in

healthy tissue

Where does it belong?…

n  Exercises for rehabilitation n  Strength training n  Aligning tissue with stretching n  Manual therapy n  NSAIDs, cortisone n  Hyaluronic acid, PRP n  Surgery

PRP?

Intratendinous  injections  of  autologous  conditioned  

plasma,  or  platelet  rich  plasma  with  or  without  WBC  

enrichment  for  patellar  tendinopathy  

A  mul&-­‐centre,  double-­‐blind,  randomized  controlled  trial  *Alex  Sco*1,  *Kim  Harmon2,  Roald  Bahr3,  Lars  Engebretsen3,  Robert  LaPrade4  1.  Department  of  Physical  Therapy,  University  of  BriJsh  Columbia,  Canada  2.  Departments  of  Family  PracJce,  Orthopaedics  and  Sports  Medicine,  University  of  Washington,  USA  3.  Oslo  Trauma  Research  Centre,  Norway  4.  Steadman  Clinic,  Vail,  USA    

EBM: Definition

Integrate current “best evidence”

from clinical research

with individual clinical expertise

and patient preferences

in making decisions about the care of individual patients

Rosenberg W & Donald A. BMJ 1995; 310:1122-6

The Oslo Sports Trauma Research Center has been established at

the Norwegian School of Sport Sciences through generous grants from the Royal Norwegian Ministry of Culture, the South-Eastern Norway Regional Health Authority, the International Olympic Committee, the Norwegian Olympic

Committee & Confederation of Sport, and Norsk Tipping AS