Cornell University College of Veterinary Medicine Evolution of PRP and stem cells Lisa A. Fortier, DVM, PhD, DACVS James Law Professor of Surgery laf4@cornell.edu Disclosures: Arthrex Consultant, VRN Consultant, Scientific Board Kensey Nash
Disclosures • Consultant: Arthrex, Veterinary Recommended Nutraceuticals, TissueGen • Royalties: Arthrex • Scientific Board: Kensey Nash
Goal of biologics • Repair, restore, regenerate tissue • Reduce pain, restore function Evidence: OA - strong Tendon (upper > lower) - modest Muscle - weak
What is PRP? • No consensus on definition • Growth factors released from platelet α -granules (TGF, PDGF, VEGF, BMPs) • Some is good −> more is better
WBC - degrade normal matrix Platelets - more is not better Platelets WBC ↑COL1A1:COL3A1 ↑MMP -3 ↑COMP ↑MMP -13 9 IL-1B (pg/mL) R² = 0.6459 8 ↓MMP -3 ↓COL1A1:COL3A1 7 6 ↓MMP -13 ↓COMP 5 4 McCarrel , Fortier JOR, 2010 Blo… 3 2 1 0 Platelet: Platelets 0 10 20 30 (10 3 /µl) WBC neutrophils… ratio 2000:1 500 2000:1 1500 200 2000:1 August 2011 AJSM NA NA McCarrell, Fortier, Minas. JBJS 2013 Yoshida, Murray JOR 2013 Boswell, Fortier, Minas. AJSM 2013
More is not better • Synoviocytes – Assirelli, Knee Surg Sports Traum Arthosc 2014 • Tendon – Cross, AJSM 2015 • ACL – Yoshida, JOR 2014. JOR 2011 • Meniscus, cartilage – Kisiday, Cartilage 2012 • Pain/function – Cole, ICRS 2015
PRP and OA pain TNF- α in “joint fluid” 12 A 10 TNF- α ( pg/ml) B 8 B 6 4 2 0 Control ACP HA HA in synoviocytes MMP 13-in synoviocytes 1.4 0 log HAS-2 Fold Change over A log MMP-13 Fold Change over 1.2 Control ACP HA -0.2 A 1 -0.4 Control 0.8 A Control 0.6 -0.6 0.4 B -0.8 0.2 B -1 0 Control ACP HA B -1.2 Sundman, AJSM 2014 Duif C. Arch Orthop Thaum Surg 2015
Group 2: =3 Group 1: <3 A I B A K C D J E L M F A H G N O Cross, AJSM 2015 Quantitative strain elastography B
PRP and BMC recruit MSCs PDGF PRP Holmes PLOS ONE 2017
Is BMC just PRP with a few MSC? BMC PRP PRP in femoral condyle BMC in femoral condyle Cassano KSSTA 2016
IL-1ra / Orthokine / IRAP BMA BMC-A BMC-B WB PRP MSC + +++ ++ - - TGF- β1, PDGF + +++ ++ + +++ Il- 1β, IL -8 + ++ ++ - - Reported IRAP concentrations
Fallen stem cell paradigms Fortier, Tuan. Small Animal Surgery, 2011 Bunnell. Stem Cell Res and Therapy, 2010.
MSC licensing / activation Cassano, Vet Imm 2017 Cassano, SSRT, 2018 K English, Imm and Cell Bio, 2013 Fortier, Sports Health, 2017
MSC in PTOA
OC histology – cartilage and subchondral bone are protected - impact + impact - impact + impact control control MSC MSC
What we now know • MSCs mitigate PTOA • They are not immunopriveledged • They don’t polarize • Activation makes them super stem cells – Regardless of source Schnabel Goodalde Hill Cassano
Rehabilitation basics Pressage 50 µm 50 µm Injured
Acknowledgements
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