INTRA ARTICULAR GROWTH FACTORS AND CARTILAGE REPAIR

HENRIQUE JONES – PORTUGUESE AIR FORCE HOSPITAL - LISBON

www.henriquejones.pt

John Hunter - 1743

Hippocrates – 400 BC

“Bone, cartilage, nerve, or the prepucewhen divided, are not regenerated, nordo the parts reunite.”

“From Hippocrates to the present age, it isuniversally allowed that ulcerated cartilageis a troublesome thing and that, oncedestroyed, it is not repaired. “

ANABOLICS

CATABOLICS

CARTILAGE BALANCE

THE MAIN PROBLEM OF CARTILAGE – CHONDROCYTE DISEASE

Growth Factor Skeletal Muscle Hyaline Cartilage Meniscus Ligament Bone

IGF-1 + + + + +

bFGF + + + + +

NGF + - -

PDGF - - +

EGF - + + +

TGF-alpha - + -

TGF-beta + + + + +

BMP-2 + + +

+ = positive effect; - = no or negative effect; blank = not testedIGF-1 = insulin-like growth factor-1; bFGF = basic fibroblast growth factor; NGF = nerve growth factor; PDGF = platelet-derived growth factor; EGF = epidermal growth factor;TGF = transforming growth factor; BMP-2 = bone morphogenetic protein-2

GROWTH FACTORS ACTION IN TISSUES

Hyaline Cartilage

+

+

+

+

+

PRP* (ng/ml)

PDGF 133 - 250

TGF beta 170 - 470

VEGF 1-7

EGF 0.47

IGF-1 60 -100

GROWTH FACTORS CONCENTRATION IN PRP

* From diferent studies

Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee

OA: a retrospective cohort study.

Sánchez M, Anitua E, Azofra J, Aguirre JJ, Andia I.

Unidad de Cirugia Artroscópica "Mikel Sanchez", Vitoria, Spain. 2008 Sep-Oct;26(5):910-3.Clin Exp Reumathology

CONCLUSIONS: Although these preliminary results need to be evaluated in a randomized clinical trial, they provide

useful information about the safety of PRGF and open new perspectives on autologous treatments for joint diseases.

BioDrugs. 2005;19(6):355-62. Novel biological approaches to the intra-articular treatment of osteoarthritis.

Evans CH. Center for Molecular Orthopaedics, Harvard Medical School, Boston, Massachusetts 02115, USA.

cevans@rics.bwh.harvard.edu

Alternatively, instead of injecting a heterogeneous, incompletely characterized mixture of native molecules into the

joint, it is possible to inject recombinant growth factors and cytokine antagonists. None of these are in routine clinical

use, but promising preliminary human trials have been performed with insulin-like growth factor-1 and the interleukin-

1 receptor antagonist. It is possible that sustained intra-articular production of such factors could be achieved by

gene transfer. Although gene therapy for osteoarthritis is not yet a clinical reality, the first human trial should begin

next year.

Ann Rheum Dis 1994;53:593-600 doi:10.1136/ard.53.9.593

Research Article

In vivo protection against interleukin-1-induced articular cartilage damage by transforming growth factor-beta 1: age-

related differences.

H M van Beuningen, P M van der Kraan, O J Arntz, W B van den Berg

CONCLUSIONS--TGF-beta 1 aggravates IL-1 induced knee joint inflammation, but counteracts the deleterious effects

of IL-1 on articular cartilage proteoglycan synthesis and content. The data indicate that TGF-beta 1 could play an

important part in articular cartilage restoration after IL-1 induced proteoglycan depletion.

Autologous Plasma Rich in Growth Factors (PRGF) Treating the Symptomatic Knee OA

Verified by Biotechnology Institute IMASD, February 2010

First Received: October 30, 2008 Last Updated: February 2, 2010 History of Changes

PurposeThe purpose of this study is to evaluate the efficacy and safety of PRGF infiltrations in the treatment of knee osteoarthritis.

Platelet-rich plasma: intra-articular knee injections produced favorable results on

degenerative cartilage lesions Journal Knee Surgery, Sports Traumatology, Arthroscopy

Volume 18, Number 4 / April, 2010

Elizaveta Kon1 , Roberto Buda2 , Giuseppe Filardo1 , Alessandro Di Martino1 ,

Antonio Timoncini2 , Annarita Cenacchi3 , Pier Maria Fornasari3 ,

Sandro Giannini2 and Maurilio Marcacci1 Volume 18, Number 4 / April, 2010

Conclusion: PRP injections is safe and may be useful for the treatment of early

degenerative articular pathology of the knee – pain, function, quality of life.

The Journal of Bone and Joint Surgery (American) 86:455-464 (2004)

© 2004 The Journal of Bone and Joint Surgery, Inc.

Autologous Chondrocyte Implantation Compared with Microfracture in the Knee . A Randomized Trial

Gunnar Knutsen, MD1, Lars Engebretsen, MD, PhD2, Tom C. Ludvigsen, MD2,

Jon Olav Drogset, MD3,Torbjørn Grøntvedt,MD, PhD3, Eirik Solheim, MD, PhD4,

Torbjørn Strand, MD4, Sally Roberts, PhD5, Vidar Isaksen, MD1 and

Oddmund Johansen, MD, PhD1

Conclusions: Both methods had acceptable short-term clinical results. There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point.

Autologous chondrocyte implantation versus microfracture for knee cartilage injury: a prospective randomized trial, with 2-year follow-up .Dieter Van Assche, Filip Staes, Danny Van Caspel, Johan Vanlauwe, Johan Bellemans, Daniel B. Saris and Frank P. Luyten KSSTA Volume 18, Number 4 / April, 2010

� The therapeutic role of micro fractures in small chondral defects is universally recognised regarding the intention of releasing marrow elements, including stem cells, growth factors and other healing proteins, creating a special environment for a new tissue formation.

�With this in mind, we thought of an additional external help to the healing process, with the addition of Platelet Rich Plasma, to micro fractures site, utilizing a new technique of reference and, PRP, application – the multi needle technique.

MF + GFMULTI

CATETERS

PERSONNALTHECNIQUE

Sixty nine official football players with chronic, limited, (< 3 cm2), chondral symptomatic Knee lesion,

without other relevant pathology, submitted to surgery, between 2004 and 2008, grouped in 3 different

series, concerning treatment. The first group was treated by micro fractures in association with PRP

(Group 1 – MF+AGF), the second group was treated with micro fractures alone (Group 2 – MF), and the

third group was treated by abrasoplasthy (Group 3 – AB).

THE STUDY

Subjective (60)

Pain (20)

20 -none

15 -mild, activity related

10 -moderate, activity related

5 -unable to perform sports

0 -pain at rest

Swelling (10)

10 - none

5 - sports / activity related

0 - with ADL’s

Objective (40)

Range of Motion (10)

10 - full ROM compared to opposite knee

5 - lacks 5-10 degrees flexion and/or

extension

0 - lacks > 10 degrees flexion and/or

extension

Ability to Perform Knee Bends (10)

10 - without difficulty

5 - mild discomfort

0 – unable

Ability to perform sport / work (20)

10 - no restrictions

5 - mild decrease in performance

0 - unable to compete / work at same level

Locking

10 - none

0 - intermittent locking

Effusion (10)

10 - none

5 - mild

0 - moderate to severe

Pain with Varus / Valgus stress on ROM (10)

10 - none

5 - mild

0 - moderate to severe

CHONDRAL DEFECT SCORING SCALE ( CDSS )

COMPARATIVE STUDY RESULTS : 3 ATHLETS SERIES

3 SERIES CHARACTERISTICS

SERIES SÉRIE 1 MF+MC

SÉRIE 2MF

SÉRIE 3ABRASATION

AGE (MEDIA) 25.2 28.6 24.2

MAJORSYMPTOMS

PAIN / SWE/FI PAIN/FI/SWE PAIN/FI/SWE

CDSS BEFORE (MEDIA)

55 65 68

CDSS +/- 18 MONTHS( MEDIA)

85 80 83

SEX 21M – 2W 19 M – 4 W 20M-3W

LOCATION IC 19-EC3-PAT1

IC19-EC4 IC18-EC5

COMPARATIVE STUDY : 3 ATHLETS TREATMENT SERIES

BEFORE SURGERY 1 YEAR AFTER SURGERY

EVOLUTION 1 YEAR AFTER SURGERY

1 YEAR AFTER SURGERY

FOOTBALL WITHOUT COMPLAINS OR LIMITATIONS

CARLA , 15 YEARS OLD ( PAIN + SWELLING + FUNCTION DISABILITY)

3.5 MONTHS

RESULTS

�The injuries were classified according Outerbridge classification and the results were validated with Chondral Defect Scoring Scale(CDSS), clinical and imagiologic evaluation.

�The present study demonstrates that the micro fractures associated with PRP (Autologous Growth Factors) had mean CDSS scores at 18 months significantly (p<0.01) better than the other two groups, although the mean values, before treatment, were above the other two groups. The clinical and imagiologic findings show a good or very good evolution with return to competition, the same level, in 91 % of the cases.

�To the author these results confirm the positive effects, and better results, regarding literature, with the association of Autologous Growth Factors to the, well known, technique of micro fractures.

DISCUSSION

� In cases of, Outerbridge grade I e II symptomatic, limited, lesions, the tratament could be the tradicional Abrasationplasty and/or Microfractures, alone, but , mostly in grade II, the association of GF gives a better prognosis and is hightly recomended .

� In cases of, Outerbridge grade , III, and even IV, symptomatic, limited lesions the treatment should be Microfractures in association with PRP ( Growth Factors ).

� The association of GF in the MF thecnique seems to show better results, mostly in grade III injuries, comparing, isolated MF as shown, in this and other, authors studies.

RECOMMENDATIONS

CONCLUSIONS OF THIS STUDY

� Despite all the insufficiencycies of this study, it seems that, based on clinical findings, imaging studies and clinical evidence, that MF is a reasonable first approach treatment of limited chondral defects ( degenerative or traumatic ), even for football players.

� Return to competition it possible in an average of 3.5 to 4 months.

� More follow up, experience and comparative studies must be achieved.

� This technique does not exclude future procedures.

� The introduction of complementary GF to the technique of MF seems to improve the percentage of good results comparing with existing literature on MF alone.

� Cost effective; technically feasible ; supportive clinical data

� Does not reliably produce hyaline cartilage

� We still go on following this players and further results will come soon.

– Facilitate the natural reparación capacity– Replacement of injuried cartílago with tissues or cells that can generate matrix

• Limitations– Experimental thecniques– Hight costs– Confiability– Versatility- Understanding sub-chondral bone

– To obtain cells and tissues, implants, that answer a to local stimulation with diferentation in mature quality chondrocytes

– Production of integrated extracelular cartilaginousmatrix– Reproduction in diferent clinical scenaries

THE PRESENT AND THE FUTURE

Recently we apply Mesofol as selant. We begin now covering with fibrine glue and collagen membrane.

“It should be clear that cartilage does not yield its secrets easily and

that inducing cartilage to heal is not simple. The tissue is difficult to

work with, injuries to joint surface, whether traumatic or degenerative,

are unforgiving, and the progression to osteoarthritis is sometimes so

slow that we delude ourselves into thinking we are doing better than we

are. It is important, however, to keep trying." Henri Mankin

THANKS FOR YOUR ATTENTION!

The author declares no conflit of interests

in this presentation!