Orthobiologics and the Athlete 2019: Update and Next steps Bert R. Mandelbaum MD DHL (hon) Co-Director of Clinical Affairs KJI at Cedars Sinai Co-Chief Sports Medicine Cedars Sinai Orthopaedic Surgery CONCACAF Chief Medical Officer and Chair Medical Committee Associate Chief Medical Officer MLS Chief Medical Officer LA Galaxy Team Physician US Soccer, LAFC Pepperdine University,
Disclosures CONCACAF Per Diem Kerlan Jobe Institute Director Ready Set Med Director Depuy Mitek J and J consultant Exactech consultant Arthrex Royalties, consultant Alter G consultant The Win Within Author Royalties
Sigi Schmid 1953-2018 Coach, Friend Mentor, colleague, partner, teacher, leader since I was a fellow! Prevention Performance Care 3
4 P Personalized Medicine
Orthobiologics Exponential Growth Moore s Law Computing data cloud dumps..genomic sequencing Artificial intelligence..facilitate knowledge Virtual and Augmented Reality.. Training Robotics.. Navigational arthroplasty etc 3 D printing.. Manufacturing of scaffolds and implants Orthobiologics and Regenerative Medicine 2020 $60 Billion 2018 100 million resistors/ 1 mm of 10 nm Intel chip
Orthobiologics
Orthobiologics Update Next steps
Mechano-Orthobiologic Paradigm 2019 Doherty 1994 Hunziker 1992 Hunziker 1992 Performance organ tissue cell/ matrix Buckwalter 1986 molecule m cm mm µm nm
Orthobiologics in Athletic Medicine correct harmony of biology, biomechanics
Orthobiologics in Athletic Medicine correct harmony of biology, biomechanics that allows healing, regeneration and adaptation to training and competitive sport
REGULATIONS AND REQUIREMENTS Title 21: Food and Drugs Part 1271: Human Cells, Tissues and Cellular and Tissue-Based Producs Safe Effective Approved PRP APPROVED BMAC NOT Stem APPROVED Cells
REGULATIONS Title 21: Food and Drugs Part 1271: Human Cells, Tissues and Cellular and Tissue-Based Producs PRP APPROVED BMAC NOT Stem APPROVED Cells
Orthobiologics in Athletic Medicine Hamstring strains Tendon Tendinopathy Repair Ligament MCL ACL repair/reconstruction tear Meniscus repair Cartilage Repair Protect Facilitate performance
BURDEN HAMSTRING STRAIN BASEBALL, SOCCER MLB $ 29 million per year MLS $ 7 million per year
Five randomized controlled trials including a total of 268 patients with grade I and II acute HS injury NO Difference with PRP for RTP
CLINICAL EVIDENCE Achilles Tendon 24 Studies PRP vs Saline (x2) PRP vs Rehabilitation Program No Significant difference between groups Acute Achilles Repair + PRP No difference - Detrimental?
CLINICAL EVIDENCE Patellar Tendon Multiple Injections ( Zayni -Yes / Kaux - No) Significant Improvement PRP vs ESWT PRP better than DN at 12 wks but not at 26wks 19 Studies One vs Multiple Injections(x2) PRP vs Shockwave Therapy PRP vs Dry Needling After ACLR - BTB Better Pain Control Better Healing at 6 mo
Video Analysis of Anterior Cruciate Ligament Injuries in the National Football League D Schub; R Brophy; T Wuerz; B Cole; T McAdams; H Silvers; N Elattrache; S Rodeo; B Mandelbaum
Show more Genomics Gene variants within the COL1A1 gene associated with reduced ACL injury in professional soccer players Cieszczyk et al 2013 91 male professional soccer players with surgically diagnosed primary ACL ruptures. control group consisted of 143 apparently healthy male professional soccer players Conclusions Frequency of COL1A1 G-T haplotype is associated with reduced risk of ACL injury
ACLR MRI Graft Maturation Radice et al. 2010 Santiago Prospective single-blinded study 50 pts w/ ACLR 25 pts w/ PRP plasma gel 25 pts w/o MRI performed between 3 and 12 months post-op Looking for homogenicity in the graft = healed Mean time to complete homogenicity 177days vs 369 days 48% reduction in healing
ACLR and PRP Systemic Review Murray et al. 2011 Graft Maturation 7 studies significantly better outcomes in the platelet groups in 4, and there were large differences in means in an additional 2 studies. Donor site 2 studies show less pain and less gap Tunnel Healing 5 studies 4 found no difference between groups. 1 showed improved early healing Clinical Outcome 3 studies found no differences, regardless of whether they had shown a beneficial effect (1 of 3) or no effect (2 of 3) of platelets on graft and tunnel healing.
2018 13 animal studies were included 6/7 studies BMSCs improved histology, biomechanics, and biochemistry at 12 w 4 studies using ACL-derived vascular stem cells improved a histology, biomechanics, and imaging within 8 weeks postoperatively 2 studies tendon-derived stem cells (TDSCs) and human umbilical cord blood derived mesenchymal stem cells (hucb-mscs) improved results In animals BMSCs, ACL derived SCs, TDSCs and UC MSCs ALL have positive effect
2014 20/43 patients with ACLR with BMAC vs Control MRI no difference Conclusion BMAC injections do not seem to accelerate graft-to-bone healing in ACL reconstruction
The Bridge-Enhanced Anterior Cruciate Ligament Repair (BEAR) Procedure An Early Feasibility Cohort Study Murray, Micheli et al 2016 Suture Repair Swivel lock to footprint Bridge TM scaffold over repair Collagen sponge and PRP 10 pts BEAR 10 HS Conclusion: The results of this study suggest that the BEAR procedure may have a rate of adverse reactions low enough to warrant a study of efficacy in a larger group of patients
Acute Proximal Anterior Cruciate Ligament Tears: Outcomes After Arthroscopic Suture Anchor Repair Versus Anatomic Single- Bundle Reconstruction Achtnich et al 2016 Repair Not For Young Athletes!!!!
PRP and Meniscal repair? No difference in reoperation rate, functional outcome measures PRP subgroup with higher KOOS pain/sports parameters MRI showed disappearance of hypersignal in 5 PRP patients (0 in control)
Articular Cartilage Injury Epidemiology 931 Athletes (40% professional) Prevalence 36% (2.4-75%) Patellofemoral: 37% Femoral Condyle: 35% Tibia: 25% General Population: 16% 14% Asymptomatic Associated Injuries: Meniscus tear :47% ACL Tear: 30% Collateral Ligament Tear 14% Flanigan, Med Sci Sports Exerc 2010
Long Term Outcome of Femoral Condyle OCA (Levy et al, CORR Jan 2013) IRB approved allograft outcomes database 1983-present: 614 allografts (536 patients) 10 years post surgery + allograft localized only to the femoral condyle: 129 allografts (123 patients) Minimum 2 years follow-up 122 allografts (116 patients)
Graft Survivorship 3.0 90% 82% 74% 65.8% 5y 10y 15y 20y 90% 82% 74% 65.8%
2013 The Effect of PRP on Autograft OATs in Rabbits Smyth, Haleem et al ICRS histology scores improved p=0.002 Bone graft integration improved p=0.004
2013 Registry study 17 condyles in 15 patients OCA transplantation without BMC and 29 condyles in 22 patients who underwent OCA transplantation with BMC BMAC group had significantly better graft integration
CASE 1 Left knee pain in swelling HPI: 25 y/o professional soccer and South American National team player RX PRP and HA. PMH: Left Knee Arthroscopy 2015 Lateral Meniscal tear. S/P ACLR Right knee 2016
Chondropeniac decline professional 25 y/o soccer player Outcome in progress
CASE 2 Left knee pain and swelling HPI: 29 y/o professional soccer team player. Missed 4-6 weeks Treatment :core rehab, medial unloader brace, PRP, BMAC, HA injections ONLY able to return with limited availability/minutes per game
RADIOGRAPH S
Persistence of Bone Marrow Lesion Gomespereira, V itor, Juninho 200988522 1 /8 /1 9 8 9 2 7 Y E A R M H MRI OCT 2017 Radioimagen Medica Gomespereira, Radioimagen Medica V itor, Juninho 200988522 O U T SI DE KN E E M RI 1 T2W_TSE (Dup) /8 /1 9 8 9 2 7 /4 /2016 11:34:05 A 7 M Y E A R M 2016070510494642 --- H Radioimagen Gomes pereira, Medica V itor, Juninho O 200988522 U T SI DE KN E E M RI 1 /8 /1 T1W_TSE 9 8 9 (Dup) 7 /4 /2016 27 YEAR 11:42:32 A M 2016070510494642 M --- H Radioimagen Medica O U T SI DE KN E E M RI PDW_TSE _SPIR (Dup) 7 /4 /2016 11:45:57 AM 2016070510494642 --- LO C : 6 7.1 0 T H K: 2.5 0 SP : 3.3 6 FFS LO C : 5 4.1 4 T H K: 2.5 0 SP : 3.8 7 FFS LO C : 5 3.7 7 T H K: 3 SP : 3.5 8 FFS A R P R L L SE N SE -Knee-8 N E X:3 E C : 1 SE FA : 9 0 T R: 2 9 7 5.2 5 T E : 1 0 0 A Q M : 3 0 4 \2 4 1 P age: 2 1 of 2 4 F SE N SE -Knee-8 N E X:2 E C : 1 SE FA Z: : 1 9 0 T C : 7 9 R: 0 5 7 7.2 9 T W: 1 3 7 E 3 : 2 0 A DFO V :15x15cm Q M : 3 0 4 \2 4 3 P I M : 2 1 SE : 6 0 age: 1 1 5 of 2 4 F SE N SE -Knee-8 N E X:1 E C : 1 SE Z: 1 FA : 9 0 C : 4 5 0 T R: 1 5 0 0 W: 7 8 2 T E : DFO 1 6.5 V 0 :15x15cm AQ M : 201\256 I M : 1 5 SE : 8 0 1 P age: 1 6 of 2 4 F Z: 1 C : 8 6 0 W: 1 4 9 4 DFO V :15x15cm I M : 1 6 SE : 9 0 1
NOV 2017: L KNEE SCOPE 1. Left knee medial Femoral Condyle and Medial tibial plateau chondroplasty 2. Left knee arthroscopic medial meniscectomy 3. Left knee intra-articulate injection to the medial compartment with bone marrow aspirate concentrate, BMAC, utilizing Arthrex Angel System
Outcome POOR Can not play and retired!
volving Concept. Chondropenia The Journey Normal Articular Cartilage Loss of volume articular cartilage Osteoarthritis
But cartilage is master of the athletic career
Harmonization Regenerate, Repair or Reconstruct, restore Prevention, Orthobiologic and Optimal Repair and Reconstructive Surgery
Orthobiologics 2019 Chondroprotection and Chondrofacilitation.. OA Disease Interventions?Modifying Corticosteroids +/- Microspheres GS/CS Hyaluronic Acid PRP Cytokine Modulation IL-Ira Inhibition of Inflammatory Response Stem Cell type procedures Adipose derived Homologous? BMAC Allogeneic stem cells Induced pluripotential cells Amniotic Fluid Estrogens Wnt pathway inhibitors Kruger J Orthop Res 2011 Strauss AJSM 2009 Fortier CORR 2011 Kuo OA Cartilage 2006 Steinert J Orthop Res 2003 Yamaoka Cell Prol 2010 ideal adjuvant combination?
A Multicenter Study of Early Anti-inflammatory Treatment in Patients With Acute ACL Tear Lattermann et al 2017 49 patients randomized to 4 groups Triamcinolone vs Placebo PROs and synovial biomarkers increases in C-telopeptide of type II collagen(ctx-ii significantly greater) in the placebo group Conclusion PTOA impacted by early intervention with an antiinflammatory agent that affects biomarkers of chondral degeneration
Chondroprotection and the Prevention of Osteoarthritis Progression of the Knee A Systematic Review of Treatment Agents Gallagher, Ciccotti et al 2015 GS/CS may protect joint cartilage and delay OA progression
Hyaluronic Acid Rationale Physiology:PGs and GAGs bind to collagen mesh and aid in hydration Biomechanical: HA is for shock absorption and lubrication aging and OA concentration and MW Therapeutic Response Decrease inflammatory response and improve viscoelastic properties (Abatangelo 89 Clin Ortho. Rel Res.) >chondrocyte density,>territorial matrix> metabolism ( Guidolin et al OA Cartilage 2001) Protects cartilage degeneration after menisectomy Enhances synthesis of GAGs ( Ameil ORS 2001)
PRP 1.0 1507 unique proteins in platelets GROWTH FACTORS PD-EGF platelet-derived epidermal growth factor PDGF A + B platelet-derived growth factor TGF-β1 transforming growth factor IGF-I, II insulin-like growth factor VEGF, ECGF vascular endothelial growth factor, endothelial cell growth factor bfgf basic fibroblast growth factor FUNCTION Cell growth, recruitment, Differentiation, skin closure, Cytokine secretion Potent cell growth, recruitment Blood vessel growth, granulation Growth factor secretion; matrix formation with BMPs (collagen and bone) Blood vessel (±), collagen synthesis, Growth inhibition, apoptosis (cell death), Differentiation, activation Cell growth, differentiation, recruitment, Collagen synthesis with PDGF Angiogenesis, Mitogenesis, Cell growth, migration, new blood vessel growth Anti-apoptosis (anti cell death) Chemotaxis, Cell growth, Cell migration, blood vessel growth Growth factors positive effect cartilage metabolism and regeneration Synovium, Meniscus, chondrocytes Akeda K et al. Osteoarthritis Cartilage. 2006 Wu W et al. J Oral Maxillofac Surg. 2007 Frisbie D et al. Am J Vet Res. 2007 Saito M et al. Clin Exp Rheumatol. 2009
META ANALYSIS COCHRANE REVMAN CHAHLA, MANDELBAUM 2018 PRP 2.0 PRP vs HA WOMAC 6mo PRP vs HA WOMAC 12mo
Hyaluronic acid induces the release of growth factors from platelet-rich plasma Lio et al Asia Pacific Sports Med and Arthroscopy 2016 PRP 3.0 HA and PRP Combinations induces the release of TGF B1 and PDGF factors from PRP What is the ideal adjuvant combination?
Pilot HA plus PRP 2018 unresponsive to HA respond well to combinations in French Multicenter
Next Steps Customization PRP 4.0 1 VEGF Noggin TGF B1 Block Vessel Formation Cartilage VEGF 2 Noggin VEGF TGF B1 Noggin TGF B Muscle TGF B1 3 VEGF Noggin Block Fibrosis Stimulate Vessel Formation Bone TGF B1 Block Noggin
THE ORTHOBIOLOGIC FAMILY No Evidence PRP BMAC Stem Cells
43 pts (Iran) randomized, triple-blind, placebocontrolled RC IA implantation of 40 10 6 autologous MSCs (Manipulated )in knee OA MSCs provided significant pain relief over 6 months versus placebo
THE ORTHOBIOLOGIC FAMILY No Evidence PRP BMAC Stem Cells
2014 A randomized, double blind, controlled study of adult human mesenchymal stem cells delivered via intra-articular injection to the knee joint following meniscectomy C. Thomas Vangsness Jr., MD, David Fox, MD, David Dellaero, MD, David Griffin, MD, Jack Farr, MD, Joel Boyd, MD, John O Donnell, MD Stem cells NOT ready for prime time.. May be inferior?
VAS improvement over baseline (mm) VAS Stem Cells PRP 60 50 40 30 20 10 0 6 weeks 6 months 1 year 2 years Control Group A Group B Improvement in VAS Pain Score through 2 years post meniscectomy surgery in patients with evidence of cartilage degeneration on MRI. Control: HA; Group A: 50 x 10 6 hmscs; Group B: 150 x 10 6 hmscs. Look about the same as PRP data!!!
Sex differences, Hormones and Receptors Opportunity?
ER ά Cartilage 2019 Synovial Fluid Estrogen /Test Cytokines IL-1,6 MMP TNF SZP PRGF 4 Lubricin HA SAPL ERß ER ά 36,46,66 AR PR-A PR-B ERß ER ά 36,46,66 ER #s varies with Menstrual Cycle, Pregnancy, Menopause ACL tear and OA AR
Estrogen reduced mechanical injury cell death Imgenberg et al 2012 17 Beta Estradiol E2 role on Cows explants Single load compression strain 50% 96 hours cell death 17 Beta Estradiol E2 reduces cell death and releases GAG
Estrogen Replacement MRI demonstrates > cartilage volume Wluka Ann Rhem Dis 2001 81 post menopausal women 41 ERT x 5 years MRI Articular Cartilage Volumes ERT 7.7% greater cartilage volume Opportunity?
2018 Significant Improvements of WOMAC and Joint space narrowing SM04690 small molecule Wnt pathway inhibitor in development potential DMOAD
Supportive devices Cane Wedge insoles (or HAA pads) Rubber sleeves Unloading braces
Therapeutic exercise Pool and swimming Advantage: weight loss Isometric, then isotonic and isokinetic Flexibility Pilates Yoga Bike Unloading treadmill Elliptical trainer
Weight reduction Sound Health Solutions By pass surgery Eades Protein Power
Orthobiological Harmonization April 5 2017 Man United
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The Orthobiogical Sports Doctor s prayer Ability to help when we can, The judgment to know when we can and can not help, The wisdom to know the difference! -BRM
The Orthobiogical Sports Doctor s prayer DO NOT exploit the gap between hope and Knowledge -BRM
Orthobiologics in Athletic Medicine 2019 BRMORTHO@Gmail.com @MandelbaumMD right, or correct comprehensive harmony with biomechanical prevention, rehabilitation, biological intervention, that allows healing, regeneration and adaptation to training and competitive sport and performance optimization
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PRP for Hamstring Muscle injuries RCT Shariff et al Kuala Lumpur, Malaysia 2014 28 patients HS Strain RCT PRP ( single)+ Rehab vs rehab PRP full recovery 26.7 days control 42.7. ( p =0.02) Pain severity scores less