Platelet Rich Plasma Update - American Shoulder And Elbow
Orthobiologics: The Evolving Frontier Disclosures Bone Marrow Aspirate Concentrate March 2015 New Kid on the Block AAOS/AOSSM Specialty Day March 28, 2015 Las Vegas, Nevada Kevin D. Plancher, M.D., M.S.1-2 Stephanie C. Petterson, MPT, PhD3 Allison Green, PhD3 Royalties from Publishers Medical/Orthopaedic Publications Editorial/Governing Board 1Clinical Professor, Albert Einstein College of Medicine Orthopaedics & Sports Medicine, New York, NY 3Orthopaedic Foundation, Stamford, CT 2Plancher Saunders/Mosby-Elsevier; Thieme American Journal of Orthopedics; Arthroscopy: The Journal of Arthroscopic and Related Surgery; Operative Techniques in Sports Medicine Board Member/Committee Appointments for a Society AAOS; ASES; AANA; ISAKOS; EOA; NY Chapter Arthritis Foundation; NY County Medical Society – Government Affairs Principal Investigator - Clinical Trials Funding, Fellowship Pfizer; Zimmer; Anika Therapeutics Arthrex; ConMed Linvatec; Zimmer © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate New Kid on the Block - BMAC Viscosupplementation Advantages AAOS - Strong Evidence Against AANA - “AAOS Missed the Mark”? Do Growth Factors Exist? Nucleated Cells Platelet-Rich Plasma - 2014 Mesenchymal Stem Cells MSCs Hyaluronic Acid New Kid on the Block - BMAC Meta-Analysis - Poor Evidence Animal Studies Human Studies • Great • Plantar Fasciitis - No Improvement • Good Potential • Chronic Lateral Epicondylitis - No Improvement ▪ No Evidence • Rotator Cuff Osteogenic (Bone) Potential Animal Studies Human Studies • Great - No Improvement • ACL Reconstruction • Good Potential - No Improvement • Achilles Tendinopathy/Rupture - No Improvement • Patellar Tendinopathy - No Improvement 1.AAOS Treatment of Osteoarthritis of the Knee, Evidence-Based Guideline. 2nd ed. 2013. Available at http://www.aaos.org/research/guidelines/TreatmentofOsteoarthritisoftheKneeGuidelin 2.Sandrey MA. Autologous Growth Factor Injections in Chronic Tendinopathy. J Athl Train.2014;49(3):428-430. 3.de Vos RJ, et al. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014; 48(12):952-6. 4.Moraes VY, et al. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2014; 29;4:CD010071. © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Limited Research Cost No Long Term Studies $1200-2000 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Animal Studies Great Results Full Thickness Chondral Defect Horses1 Progenitor Cells Differentiate To: • • • • Disadvantages Bone Marrow Aspirate Concentrate Stem Cells - What Are They? Mesenchymal Stem Cells 3-8x Concentrated in Aspirate Chondrogenic (Cartilage) Potential Osteoblasts Chondrocytes Myoblasts Adipocytes MFx Vs. Decalcified CorticalCancellous Bone Matrix • Hyaline-Like Articular Cartilage Repair • Biomechanical Properties Like Normal Cartilage Bone Marrow Adipose Tissue Synovial Tissue Peripheral Blood Periosteum Umbilical Cord Blood Infrapatellar Fat Pad 1.Veronesi et al. Clinical Use of Bone Marrow, Bone Marrow Concentrate, and Expanded Bone Marrow Mesenchymal Stem Cells in Cartilage Disease. Stem Cells and Development 2013. 15;22(2):181-92 2.Filardo G. et al. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. KSSTA. 2013; 21:1717–1729 • Increased Filling of Defect • Greater Type II Collagen Rabbits2 - 2014 Sources Microfracture Vs. MFx + BMAC Generalized Osteoarthritis Sheep3 Isolated Meniscus Tear Slowed Cartilage Progression Evidence of Meniscal Regeneration Sheep4 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Full Thickness Tear Red-White Zone • Improved Meniscal Healing Rabbits5 Full Thickness Tear Avascular Zone • MSCs - Improved Meniscal Repair 1.Fortier LA et al. Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. JBJS Am. 2010 18;92(10):1927-37. 2.Dai L et al. One-step repair for cartilage defects in a rabbit model: a technique combining the perforated decalcified cortical-cancellous bone matrix scaffold with microfracture. AJSM. 2014; 42(3):583-91. 3.Al Faqeh H et al. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012; 47(6):458-64. 4.Duygulu F et al. Effects of intra-articular administration of autologous bone marrow aspirate on healing of full-thickness meniscal tear: an experimental study on sheep. Acta Orthop Traumatol Turc. 2012;46(1):61-7. 5.Zellner J et al. Role of mesenchymal stem cells in tissue engineering of meniscus. J Biomed Mater Res A. 2010; 15;94(4):1150-61. © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Stem Cells - Where Do We Get Them? Sources - Autologous or Allogenic Select Donor Site Withdraw ~60cc Aspirate Centrifuge Extract Concentrate Deliver BMAC Greatest Concentration • Bone-Forming MSCs1 - 898.4±1431.5 cells/mL Other Sources One-Step Iliac Crest How Do We Do It? Anterior/Posterior Iliac Crest Full Regenerative Potential Knee • Cartilage • Meniscal Regeneration • ACL Tibial Metaphysis • 32.4±135.4 cells/mL Calcaneal Humerus2 Proximal Distal Femur • 883.9±577.6 cells/mL • 551.3±408.1 cells/mL Shoulder Elbow Hip • Arthroscopic Rotator Cuff • 7.1±17.4 cells/mL • Lateral Epicondylitis 1. 2. Hyer CF et al. Quantitative assessment of the yield of osteoblastic connective tissue progenitors in bone marrow aspirate from the iliac crest, tibia, and calcaneus. JBJS Am. 2013;95(14):1312-6. Beitzel K et al. Comparison of mesenchymal stem cells (osteoprogenitors) harvested from proximal humerus and distal femur during arthroscopic surgery. Arthroscopy. 2013;29(2):301-8. © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC • Avascular Necrosis 1.Gigante A et al. Arthroscopic knee cartilage repair with covered microfracture and bone marrow concentrate. Arthrosc Tech. 2012; 4;1(2):e175-80. Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Back to The Future? BMAC Systems *White Paper Info Biomet BioCue Arteriocyte Magellan MaroMax Harvest SmartPReP 2 BMAC Arthrex Angel Alliance Spine Cyclone Emcyte Genesis CS Nucleated Cells 7.9x 5-6x (MSCs) 3-6x 10x 7-8x 11-12x Platelets 7.2x 7.2x 4-6x 9x 7-8x 6.7x Hardware Cost (i.e. Centrifuge) None None None None None ~$1300 $1200-1900 ~$2000 $1400 $1095 15 min 16 min 40ml - 15 min 180ml 26 min 10 min 12 min Spin 2800 2nd Spin 3800 2500±150 x 1-3 min 2300±140 x 6-9 min 3800 2400 Two-Step Regulatory Issues Clinical Trial Knee Why? Expanded Grow Cells • Greater Concentration of MSCs Per Use Cost (i.e. Kit) Disadvantage Risk of Contamination 1.Wakitani S et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. 2002; 10:199-206. 2.Veronesi F et al. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2013; 22(2):181-92. 3.Xu S et al. An improved harvest and in vitro expansion protocol for murine bone marrow-derived mesenchymal stem cells. J Biomed Biotechnol. 2010; 2010:105940. Total Processing Time RPM © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC 15 min 3200 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate How Much To Inject? 3 Systems Compared 1st *Excludes International Companies BMAC Systems - 2014 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Harvest SmartPReP 2 BMAC Biomet BioCUE Arteriocyte Magellan Osteogenic, Chondrogenic Greatest Concentration After Centrifugation <1000 MSCs/mL Injected >1000 MSCs/mL Injected • All Healed Harvest SmartPReP 2 System Best Yield Smaller Volume BMA = Greater Concentration MSC 30 BMA Samples From Iliac Crest2 10cc Vs. 50cc Syringes • 3x Greater MSCs Concentration - 10mL Syringe! 40 Patients Bilateral Iliac Crest Aspiration • First 20 Harvest Vs. Biomet • Second 20 Harvest Vs. Arteriocyte 1.Hegde V et al. A prospective comparison of 3 approved systems for autologous bone marrow concentration demonstrated nonequivalency in progenitor cell number and concentration. J Orth Trauma 2014; 28(10):591-8. 60 Tibial Atrophic Non-Unions JBJS • No Healing Greatest Number Progenitor Cells >1000 MSCs/mL Threshold1 32 BMA Patients from Anterior Iliac Crest3 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC 1cc Vs. 2cc and 2cc Vs. 4cc Syringes • Larger Volume = Decrease MSC ▪ Diluted with Peripheral Blood • 4 1cc Syringes 2x MScs than 1 4cc Syringe 1.Hernigou P et al. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. JBJS Am. 2005;87(7):1430-7. 2.Hernigou P et al. Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal tem cells. Int Orthop (SICOT). 2013;37:2279-2287. 3.Muschler GF et al. Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. JBJS Am, 1997;79: 1699-709. Erratum. 1998; 80:302. © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Is BMAC Safe? Systematic Review - 2013 844 Cases Indications No Reported Complications1 • No Tumors or Infections Avascular Necrosis10 Hip Knee Elbow Other Indications No Infection No Complications To Date Long Term Studies Elbow Patellar No Morbidity Injection Site Chondral Defects3,4,7 Harvest Site Chronic Tendinopathy Our Recent Series 101 Cases Rotator Cuff Repair15 Cartilage Regeneration1 Following Aspiration • 0.001% Infection • 0.001% Pulmonary Embolism - Circumstances? Pain and Swelling • Harvest Site • Injection Site Primary Indications More Data Needed 1.Hendrich C et al. Safety of autologous bone marrow aspiration concentrate transplantation: initial experiences in 101 patients. Orthop Rev (Pavia). 2009;1(2):e32. 2.Wakitani S et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med 2011; 5:146–150. 3.Peeters CM et al. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthritis Cartilage. 2013 Oct;21(10):1465-73. Spinal Fusion11 Chronic Wound Healing12 Ischemic Wounds2,9 Distraction Osteogenesis6,8 Delayed Union & Nonunion5,10 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Shoulder - Rotator Cuff Repair Arthroscopic Rotator Cuff Repair - 2014 Knee - Meniscal Regeneration Partial Medial Meniscectomy - 2014 45 Patients Symptomatic Ruptures Minimum 10 Year Follow-Up Faster Healing Rate - 6 Months Prevented Further Tears 100% RCR+MSC Patients 67% RCR Only Patients Intact Rotator Cuff at 10 Years • 87% RCR+MSC Patients • 44% RCR Only Patients 1.Hernigou P et al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38(9):1811-8. © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC - P=0.04 1.Vangsness CT et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. JBJS Am. 2014;96(2):90-8. 2.APiontek T et al. ll-arthroscopic technique of biological meniscal tear therapy with collagen matrix. Pol Orthop Traumatol. 2012; 31;77:39-45. 3.James EW et al. Repair of a complete radial tear in the midbody of the medial meniscus using a novel crisscross suture transtibial tunnel surgical technique: a case report. KSSTA. 2014 Jun 3. [Epub ahead of print] © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Chondral Defects2 - 2014 25 Patients BMAC+Collagen Scaffold Matrix 3 Year Follow-Up Minimum ICRS Grade 4 - Full Thickness Defect • Lesion Size 8.3 cm2 Complete Filling of Defect in 80% of Patients Hyaline-Like Cartilage Osteoarthritis Medial Compartment1 56 Patients Significant Increase in Meniscal Volume (>15%) • 1 Year Follow-Up - P=0.022 Significant Reduction in Pain • 2 Year Follow-Up Knee - Chondral Defects Meniscectomy + MSCs: Isolated Repair Vs. Repair + MSCs Isolated Meniscectomy Meniscectomy with MSCs • Allogenic MSCs 7-10 Days Later Single Row Rotator Cuff Repair Randomized, Double-Blind, Controlled Study1 • 1.5-3.5cm 1. Giannini S et al. Cartilage repair evoluation in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury. 2010;41(11):1196-203. 2. Iafrati MD et al. Early results and lessons learned from a multicenter, randomized, double -blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg. 2011;54(6):1650-8. 3. Gobbi A et al. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. AJSM. 2014;42(3):648-57. 4. Wakitani S et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 4 5 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 2011;5(2):146-50. 5. LeNail LR et al. Percutaneous grafting with bone marrow autologous concentrate for open tibia fractures: analysis of forty three cases and literature review. Int Orthop. 2014;38(9):1845-53. 6. Lee DH et al. Bone marrow aspirate concentrate and platelet-rich plasma enhanced bone healing in distraction osteogenesis of the tibia. CORR. 2014;472(12):3789-97. 7. Wakitani S et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in oste oarthritic knees. Osteoarthritis Cartilage. 2002;10(3):199-206. 8. Gessman J et al. Regenerate augmentation with bone marrow concentrate after traumatic bone loss. Orthop Rev (Pavia). 2012;4(1):e14. 9. Benoit E et al. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design. J Transl Med. 2011; 9:165. 10.Hendrich C et al. Safety of autologous bone marrow aspiration concentrate transplantation: initial experiences in 101 patients. Orthop Rev (Pavia). 2009;1(2):e32. 11.Vadala G, et al. Use of autologous b one marrow cells concentrate enriched with platelet-rich fib rin on corticocancellous b one allograft for posterolateral multilevel cervical fusion. J Tissue Eng Regen Med. 2008;2(8):515-20. 12.Nishimoto S, et al. Impacts of bone marrow aspirate and peripheral blood derived platelet-rich plasma on would healing in chronic ischaemic limb. J Plast Surg Hand Surg. 2013;47(3):169-74. 13.Jyotsna M, et al. Autologous bone marrow-derived progenitor cell myocardial delivery for recent myocardial infarction patients following early angioplasty: results from a pilot study. Cardiovasc Revasc Med. 2006;7(4):217-21. 14.Konstanty-Kalandyk J, et al. The combined use of transmyocardial laser revascularization and intramyocardial injection of bone-marrow derived stem cells in patients with end-stage coronary artery disease: one year follow-up. Kardiol Pol. 2013;71(5):485-92. 15.Mazzocca AD, et al. Rapid isolation of human stem cells (connective progenitor cells) from the proximal humersu during rotator cuff surgery. AJSM. 2010;38(7):1438-47. Elbow - Lateral Epicondylitis Chronic Lateral Epicondylitis1 2014 30 Patients Single Injection Significant Decrease 2 Year Follow-Up Varus Alignment - 9° Patient-Rated Tennis Elbow Evaluation (PRTEE) Scores • Measures Pain, Function, and ADLs • Higher Scores = Higher Dysfunction Pre-Injection - Baseline Post-Injection – 3 Months High Tibial Osteotomy with Microfracture - All 28 Patients - Isolated Procedure or 28 Patients + Intraarticular Injection MSCs Significant Functional Improvement in Patients with MSCs • 72.8 ± 6.97 • IKDC • Lysholm • Tegner 1.Wong KL et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing HTO: a prospective, RCT with 2 years’ follow-up. Arthroscopy. 29(12):2020-8. 2.Gobbi A et al. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC defects of the knee. AJSM. 2014; 42(3):648-57. Untreated • 14.86 ± 3.48 - P<0.0001 No Adverse Events 1.Singh A et al. Bone marrow injection: A novel treatment for tennis elbow. J Nat Sci Biol Med. 2014;5(2):389-91. © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Ankle - Osteochondral Defect Focal Talar Dome Lesions 25 Patients Improved Functional Scores Hip - Avascular Necrosis Follow Up - Avg 5 Year Femoral Head Osteonecrosis - 2014 AOFAS • 7.1±17.2 to 92.6±10.5 - P<0.0005 • 82% Improvement 1 Year 219 Hips Meta-Analysis Results - 3 Years - 2nd Look Bone Marrow-Derived MSC Injection Core Decompression Higher Harris Hip Scores • Pooled Weighted Mean Difference = 8.69 - 95% CI: 3.76-13.62 - P<0.01 Harvested Cartilage • 100% Patients - Hyaline Cartilage in the Defect Less Progression of Osteonecrosis • Pooled Odds Ratio = 0.11 - 95% CI: 0.03-0.43 - P<0.01 1.Giannini S et al. Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. 2010. Injury 41:1196–1203 © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC 1.Li X et al. Comparison of bone marrow MSCs and core decompression in treatment of osteonecrosis of the femoral head: a meta-analysis. Int J Clin Exp Pathol. 2014;7)8):5024-30. Orthobiologics Orthobiologics Bone Marrow Aspirate Concentrate Bone Marrow Aspirate Concentrate Our Series Preparation - BMAC Promising Clinical Evidence One-Step Systems Regenerate Knee, Shoulder, Elbow, Hip and Ankle Hyaline-Like Cartilage Meniscus • Knee2-4 Pain Free Return to Sport Recreational/ Professional Athlete Conclusion 40-60 Year Old © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Tennis Skiing Basketball Running Complications Manage Patient Expectations No Complications Great Promise For Restoration Of Anatomic Architecture Rotator Cuff Healing Improved Minimal to None New Treatment Variable Results Cost? Future Directions © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC Insurance Company Coverage? 1.Hegde V et al. A prospective comparison of 3 approved systems for autologous bone marrow concentration demonstrated nonequivalency in progenitor cell number and concentration. J Orth Trauma. 2014; 28(10):591-8. 2.Gobbi A et al. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. AJSM. 2014; 42(3):648-57. 3.Giannini S et al. Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury 2010; 41:1196–1203 4.Vangsness CT et al. Adult human mesenchymal stem cells delivered via intraarticular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. JBJS Am. 2014;96(2):90-8. More Clinical Evidence Needed Human RCT in BMAC Vs. PRP Regeneration of Other Tissues • Tendons and Ligaments © Copyright 2015 Plancher Orthopaedics & Sports Medicine PLLC
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