Eficacia de los Tratamientos Biológicos: Factores de ... · Eficacia de los Tratamientos...

@RamonCugat

Barcelona, Enero 2014

Eficacia de los Tratamientos Biológicos:

Factores de Crecimiento y Células

Mesenquimales en lesiones del deporte

MEDICINE DOCTORS

Ramon CUGAT

Xavier CUSCÓ

Pedro ÁLVAREZ

Óscar ARES

Juan Manuel BOFFA

Eduardo MAURI

Betina NISHISHINYA

Marta RIUS

Esther SALA

Roberto SEIJAS

Gilbert STEINBACHER

Montse GARCIA-BALLETBO

Ana WANG-SAEGUSA

Silvia RAMON

Josep VERGES

BTI

Eduardo De ANITUA

Mikel SÁNCHEZ

VETERINARY DOCTORS

.- IVOT:

Alex TARRAGÓ

Ángel DURAN

Diego LÓPEZ

Javier TOTUSAUS

.- Universidad CEU-UCH de Valencia:

José Mª CARRILLO

Joaquín SOPENA

Mónica RUBIO

Mariluz ORTIZ

Mireia GARCIA

Belén CUERVO

Deborah CHICARRO

Elena DAMIÁ

.- Universidad de Murcia:

José Joaquín CERÓN

Asta TVARIJONAVICIUTE

.- Universidad de Córdoba:

Juan Manuel DOMÍNGUEZ

Andrés FERNÁNDEZ

Mª del Mar GRANADOS

Rafael GÓMEZ

Rocío NAVARRETE

Juan MORGAZ

Setefilla QUIRÓS

Raúl ROMERO

Francisco Javier FUNES

Pilar MUÑOZ

María RODRÍGUEZ

.-Universidad de Las Palmas de Gran Canaria:

José VILAR

Manuel MORALES

.-Universidad Católica de Valencia:

Iván SERRA

Carme SOLER

FISIOTERAPEUTAS

Ferran VIDIELLA

Miguel Ángel PÉREZ

Miguel MARÍN

M Ángeles ENGUITA

Elena MORALES

Rosa TEIXIDÓ

Rafa ALCOVER

Nieves LAMA

Xavier ÁLVAREZ

Juan Carlos ALEMANY

Montserrat VERGÉS

Joan BOSCH

Nahor GARCÍA

Lorena PAHINO

Ixchel MONTSERRAT

PRGF - Endoret

Cells

Signaling Molecules

3-Dimensional

Matrix

Regenerative Medicine

PRGF - Endoret

Repair and Regeneration

Tissue response (time)

Haemostasia

Inflammation Angiogenesis

Cell proliferation

migration

ECM

remodelling

Anitua E. Int J Oral Maxillofac Implants 1999;14(4):529-35.

Anitua E, Sánchez M, Orive G. Adv Drug Deliv Rev. 2010;62(7-8):741-52.

Anitua E, Sánchez M, Orive G, et al. Biomaterials 2007;28:4551-4560

Cugat R, Garcia-Balletbo M. Eur Musc Rev 2010;32-35

Biomet GPS

Harvest/SmartPrep2/BMACDepuy/

Symphony II

Sorin Angel/Arteriocyte Medical

(Magellan:Medtronic, Minneapolis,MN)

Buffy coat product: concentrated

platelets + white blood cells + fractions

& minimal amount of red blood cells

Genesis CS

Choukroun’s PRF

Leucocytes & platelet rich fibrin

concentrates of platelets, leucocytes

through siphoning device

Autogel System/Smart PReP Platelet in plasma suspension with minimum

white blood cells & low concentration of platelets

Electa/Haemonetics/CATS/BRAT Platelet concentrate only

Cascade PRFM fibrinet system Platelet-rich fibrin membrane

Secquire/Arthrex ACP Manual aspiration of platelet & plasma after

centrifuging

Vivostat Platelet-rich fibrin & Fibrin sealant without

platelet

Caption Concentrated platelets without plasma

BTI. Biotechnology Institute Platelets & plasma

Are all the PRPs the same?

PRGF - Endoret

.-PRGF-Endoret® Liquid not

Activated=Fraction 1, Poor or

Superior + Fraction 2, Rich or Next to

the buffy coat

Yellowish liquid obtained after centrifugation:

Plasma with Plasmatic Growth Factors &

Platelets intact

.-PRGF-Endoret®Liquid Activated

It is generally fraction 2=Plasma with 2-2’5 times

the peripheral blood platelet concentration +

5%CaCl2

.- PRGF-Endoret® Coagulant/Clot

(Fraction 2)

It is PRGF-Endoret® Liquid (Fraction 2)

Activated & Coagulated

Alternative Version: PRGF-Endoret® Coagulant +

biological material or inorganic

.-PRGF-Endoret® Fibrin Membrane

(Fraction 1)

It is Liquid PRGF-Endoret® (Fraction 1)

Activated & Coagulated “Ex Vivo”

Plasma with concentration of platelets similar to

those of peripheral blood without red or white

cells

.-PRGF-Endoret® Supernatant Transparent yellowish liquid that bathes the

white fibrin membrane. It is a liquid preparation

with a high content of cellular signals

Formulas obtained with PRGF-Endoret®

Endoret

Anti-Angiogenic

Factors

Thrombospondin 1

Platelet Factor 4

Angiostatin

Endostatin

Tissue inhibitors of

metalloproteinases

Pro-Angiogenic

Factors

Vascular Endothelial

Growth Factor

Fibroblast Growth

Factor

Angiopoietin-1

Platelet-Derived

Growth Factor

Epidermal Growth

Factor

Insulin-Like Growth

Factor-1

Heparanase

Stromal Cell-Derived

Factor-1

Sphigosine

Phosphate

PRGF - Endoret

Tissue repair: biological processes

Stellos K et al. Platelets in regeneration. Semin Thromb Hemost 2010. 36: 175-84

Percutaneous Infiltration

Bone

In clot/coagulant form with bone graft

3 months post-op

6 months post-op

1. Nonunions treated with autologous preparation rich in

growth factors. Sanchez M, Anitua E, Cugat R, Azofra

J, Guadilla J, Seijas R & Andia I. J Orthop Trauma

2009 Jan 23(1):52-59. PMID: 19104304

2. Delayed union of the clavicle treated with plasma rich

in growth factor. Seijas R, Santana-Suárez Y, García-

Balletbó M, Cuscó X, Ares O & Cugat R. Acta

Orthopedica Belgica 2010, 76(5), 689-693 PMID:

21138228

3. Growth Factors: Application in Orthopaedic Surgery

and Trauma. Garcia-Balletbo M & Cugat R. In: Doral

MN et al. (Eds.) Sports Injuries DOI: 10.1007/978-3-

642-15630-4_116,© Springer-Verlag Berlin Heidelberg

2012

References

FERNÁNDEZ-SARMIENTO JA. “Effect of the Implementation of

PRGF® in Tendon Healing. Experimental Study in an Achilles

Tendon Rupture Model”. DOCTORAL THESIS. Universidad de

Cordoba.

.- DOMÍNGUEZ JM, FERNÁNDEZ-SARMIENTO JA, GRANADOS MM, MORGAZ J,

NAVARRETE R, CARRILLO JM, RUBIO M, GARCÍA-BALLETBÓ M, CUGAT R, MONTERDE

J, BLANCO A. Ultrastructural study of the healing process in tenotomized achilles

tendons treated with plasma rich in growth factors in sheep. Osteoarthritis and Cartilage.

20; Supplement 1, April 2012, S250-S251. ISSN: 1063-4584. Impact Factor: 3.953.

.- FERNÁNDEZ-SARMIENTO JA, DOMÍNGUEZ JM, GRANADOS MM, MARTÍN DE LAS

MULAS M, MILLAN Y, GARCÍA-BALLETBÓ M. Histological Study of the Influence of

Plasma Rich in Growth Factors (PRGF) in a Model of Tenotomized Achilles Tendon in

Sheep. KSSTA. 20, Supplement 1, May 2012, S349. ISSN: 0942-2056. Impact Factor:

1.857.

.- FERNÁNDEZ-SARMIENTO JA, DOMÍNGUEZ JM, GRANADOS MM, MORGAZ J,

NAVARRETE R, CARRILLO JM, GÓMEZ-VILLAMANDOS RJ, MUÑOZ-RASCÓN P, MARTÍN

DE LAS MULAS J, MILLÁN Y, GARCÍA-BALLETBÓ M & CUGAT R. Histological Study of

the Influence of Plasma Rich in Growth Factors (PRGF) on the Healing of Divided Achilles

Tendons in Sheep. JBJS 2013, Am95: 246-55. Impact Factor: 3.234

References

Conclusions

1) PRGF® injections produced no detectable adverse

effect on tendon healing and general health of

animals.

2) Tendons treated with PRGF® showed an

improvement in the tendon healing process both at

4 and at 8 weeks in the Achilles tendon rupture

experimental model in the study.

3) PRGF® injections produced a better

organization of collagen fibres and less intense

inflammation than infiltration with saline.

Injury: 10 September 06

PRGF® injection: 13 September 06

Muscle Medial Third of the Rectus Femoris Injury

Gastrocnemius Injury

Vastus

Lateralis

Vastus Intermedius

* *

Vastus

Lateralis

Vastus Intermedius

CASE 5

11 days

Randomised Studies

SEIJAS R, CUSCÓ X, ARES O, ÁLVAREZ P, SERRA IC & CUGAT R.

RPRGF Application at Donor Site Decreases Knee Pain in Bone Tendon

Bone ACL Reconstruction. (Pending Publication)

SEIJAS R, RIUS M, ARES O, GARCÍA-BALLETBÓ M, SERRA IC & CUGAT

R. Healing of donor site in BTB ACL Reconstruction accelerated with

Plasma Rich in Growth Factors (PRGF): a randomized clinical trial. KSSTA

2013 Nov 17

Patient No. 98

Age Range 18-65

Patient No. Group A

(Surgery + PRGF®)

49

Patient No. Group B

(Surgery)

49

Inclusion Criteria First Surgery on injured knee

Informed Consent

Total Rupture requiring ACL reconstruction

Follow Trial Controls

No previous PRGF® treatment

No Contraindications

Surgical Technique Arthroscopic ACL Anatomical Reconstruction using

Single Bundle Autograft B-PT-B AM Portal

LIGAMENT ACL Surgical Reconstruction

Study on the maturity of B-PT-B autograft and donor site

Seijas R, Ares O, Catala J, Alvarez-Diaz P, Cusco X & Cugat R Magnetic Resonance imaging evaluation of patellar tendon graft remodelling after

ACL reconstruction with or without platelet-rich plasma 2013

Weiss RA, Re LP, Rintz KG. Incidence of anterior knee pain after treatment for anterior cruciate ligament

rupture. Arthroscopy 1993;9;366

Shelbourne KD, Trumper RV. Preventing anterior knee pain after anterior cruciate ligament

reconstruction. Am J Sports Med. 1997 Jan-Feb;25(1):41-7

16% Anterior knee pain related exclusively to this surgery



A B C

D

A Open

B Closed less 50%

C Closed more 50%

D Closed

Patellar Donor Site Maturation

Seijas R Estudio de Evaluación de la Cicatrización en Ligamentoplastia de Ligamento Cruzado Anterior de Rodilla 2013

Results: Time to Full Maturity



PRGF group shows

earlier donor site

regeneration with

statistically significant

differences at 4 month

follow-up. No

statistically significant

differences were found

within tendinous

maturation and

regeneration both during

first months and beyond

6th month.

Results: Pain

PRGF® decreases pain during first months



PRGF group presents

less pain at the donor

site, with statistically

significant differences

during the first 4

months of follow-up,

with a strong trend

towards 6th month

although without

statistical significance

Results Graft Maturity

1

Hypointense

2

Mildly

Hyperintense

3

Moderately

Hyperintense

4

Severely

Hyperintense

5

Diffusely

Hyperintense



1

Hypointense

2

Mildly

Hyperintense

3

Moderately

Hyperintense

4

Severely

Hyperintense

5

Diffusely

Hyperintense

P Value

4 Months 0.003

PRGF® 4 6 20 12 7

Non PRGF® 7 19 12 9 2

6 Months 0.0001

PRGF® 1 2 9 15 22

Non PRGF® 6 11 15 14 3

12 Months 0.354

PRGF® 0 1 1 13 34

Non PRGF® 0 2 2 15 30

Results: MRI Assessment

Graft Maturity

Seijas R, Ares O, Catala J, Alvarez-Diaz P, Cusco X & Cugat R Magnetic Resonance imaging evaluation of patellar tendon graft remodelling

after ACL reconstruction with or without platelet-rich plasma 2013

4 Months PRGF® group: Statistically Significant Differences with more cases in more advanced

stages of maturation (p=0.003)

6 Months Statistically Significant Differences between groups. PRGF® group showing greater

number of cases in more advanced stages of maturation (p=0.0001)

12 Months Both groups showed complete maturation in almost all patients (p=0.354)

Results

Patellar Donor Site & Graft Maturation

Seijas R, Ares O, Catala J, Alvarez-Diaz P, Cusco X & Cugat R Magnetic Resonance imaging evaluation of patellar tendon graft remodelling after ACL reconstruction with or

without platelet-rich plasma 2013

1) PRGF group shows earlier donor site regeneration with statistically

significant differences at 4 month follow-up. No statistically significant

differences were found within tendinous maturation and regeneration both

during first months and beyond 6th month

2) PRGF group presents less pain at the donor site, with statistically significant

differences during the first 4 months of follow-up, with a strong trend towards

6th month although without statistical significance

3) PRGF group did not show differences in terms of functional return; in

general quality of life index, as well as in specific, sports return or objective

parameters such as KT-1000 or maturation grades of the graft measured with

MRI

4) More patients in the PRGF group attained higher stages of remodelling at

month 4 (p=0.003), month 6 (p=0.0001), and month 12 (p=0.354)

5) PRGF and control groups did not differ significantly in terms of age,

comorbidities, sex, height, weight, and postoperative swelling and

complications

Knee Dislocation

Knee Dislocation. PRGF Treatment

BPTB Graft Revision

7 Weeks post-Surgery

BPTB Graft Revision

14 Weeks post-Surgery

MCL Results

Pre - PRGF® Treatment

Post - PRGF® Treatment

REFERENCES:

•Cugat R, Carrillo JM, Sopena J, Tarrago A, Soler C & Serra CI.

Treatment Results of Chondral Lesions using Plasma Rich in Growth

Factors and Other Substances. Electronical Poster in ISAKOS Bi-Annual

Congress. Hollywood FL, US 2005

•Serra CI. Análisis Biomecánico e Histológico del Tejido de Reparación en

Defectos Condrales de Espesor Completo tras la Aplicación de Plasma Rico

en Plaquetas Autólogo. Estudio Experimental. Doctoral Thesis.

Universidad Cardenal Herrera CEU. Valencia, Spain 2006

•Soler MC. Análisis Macroscópico, Histólógico e Inmunohistoquímico del

Efecto del Plasma Rico en Plaquetas Autólogo en la Reparación de Defectos

Condrales en Conejo. Estudio Experimental. Doctoral Thesis. Universidad

Cardenal Herrera CEU. Valencia, Spain 2006

PCB 19 w PRP 19 w References

REFERENCES:

•CUGAT R & GARCIA M. Treatment of Chondral Lesions with Plasma-Rich Growth Factors.

Oral Presentation at the Japan Knee Society 29th Annual Meeting. Hiroshima, Japan.

2004.

•CUGAT R, CARRILLO JM, SERRA CI & SOLER C. Articular Cartilage Defects

Reconstruction by Plasma Rich Growth Factors. In Basic Science, Clinical Repair and

Reconstruction of Articular Cartilage Defects: Current Status and Prospects. Chapter 88.

Edited by Timeo. Pp:801-7. 2006.

•WANG-SAEGUSA A. Infiltración de PRGF (PRP) en OA de Rodilla. Efecto-Repercusión en la

Calidad de Vida y Función Física. Tesina para Máster en Medicina Cosmética y

Antienvejecimiento. UAB 2008.

•ZARINS B, CUGAT R & GARCIA-BALLETBO M. Platelet-Rich Plasma (PRP)-Potential

Orthopaedic Applications of Autologous Preparations Rich in Growth Factors (PRGF). Hvd

Ortho J. 2009.

•WANG-SAEGUSA A, CUGAT R, ARES O, SEIJAS R, CUSCO X & GARCIA-BALLETBO M.

Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects

on function and quality of life. Arch Orthop Trauma Surg 131: 311-7. 2010.

•ARES O & CUGAT R. Biological Repair of Knee Injuries in Soccer Players. Techniques

Knee Surg. 9: 132-8. 2010.

•CUGAT R & GARCIA-BALLETBO M. Growth Factors a brief review. Musculoskeletal Rev

5: 32-5. 2010

Cartilage

MESENCHYMAL STEM CELLS-

ADIPOSE TISSUE

• chondrocytes

• osteocytes

• adipocytes

• myocytes

• fibroblasts

http://krlos-

mundovitalkrlos.blogspot.com/2011/02/celulas-madre-ii-

parte-embrionarias-y.html

CULTIVATED ADULT STEM CELLS

http://krlos-mundovitalkrlos.blogspot.com/2011/02/celulas-madre-ii-parte-embrionarias-y.html













Animal Specie:

Canis familiaris

Number of animals: 17

Type of study: Prospective Multicentric

Clinical Study

Study groups: 2

Joints Studied:

- Coxo-femoral joint (Hip)

-Synovial hinge joint (Elbow)

-Femoro-tibial-fibular (Knee)

MATERIALS & METHODS ANIMAL MODEL

Vilar JM, Morales M, Santana A, Spinella G, Rubio M, Cuervo B, Cugat R & Carrillo JM.

Controlled, blinded force platform analysis of the effect of intraarticular injections of

autologous adypose-derived mesenchymal stem cells associated to PRGF-Endoret in

osteoarthritic dogs. BMC Veterinary Research. 2013. 9: 131-6

PRGF ADMSC + PRGF

Improvement Articular Mobility + +

Improvement Functional Limitation

(Quality of Life)

+ +

VAS owner: Pain decrease + +

VAS Veteranarian: Pain decrease + +

Owner satisfaction: Decrease Degree

of Lameness

+ +

Results

PRGF & ADMSC + PRGF improve articular function

At 6 months differences between the 2 groups do not exist

Differences more long term

Conclusions

The application of plasma rich in growth factors (PRGF®-

Endoret) in bone fractures, delayed unions and nonunions

should be seen as beneficial in the acceleration of the

healing process

Tendons treated with PRGF®-Endoret showed an

improvement in the healing process

PRGF®-Endoret injections produced a better organization

of collagen fibres and less intense inflammation

PRGF®-Endoret in ACL Injuries, accelarate healing &

decrease pain

GFs obtain hyaline-like cartilage

Muscle hypertrophy does not occur locally or systemically

after local injection of PRGF®-Endoret

Conclusions

GFs + Cells + Scaffolds + Enviroment = Good Setting

ADRCs express growth factors in response to the environment around

them

Growth factors express change as the environment changes and

promote healing through transient modulation of:

Angiogenesis

Chemotaxis

Cell proliferation & Differentiation

Synthesis of ECM

We still have a long way to go but regeneration is the path to

follow

Conclusions

www.bioregeneracion.com

www.artroscopiagc.es

www.fundaciongarciacugat.org

@RamonCugat

Eficacia de los Tratamientos Biológicos: Factores de ... · Eficacia de los Tratamientos...

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