orthobiologics in joint preservation - what is working and ... · orthobiologics in joint...
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Orthobiologics in Joint Preservation - What is working and How Would We Know?
Do you have the cells that you need?
George F. Muschler, M.D. - Cleveland Clinic
Nat Rev Rheumatol. 2013 Dec;9(12):721-30. doi: 10.1038/nrrheum.2013.141. Epub 2013 Oct 1. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Andia I1, Maffulli N.
4 - Barbour KE et al. Morb Mortal Wkly Rep 2017 March 7 - Hootman JM et al. Arthritis Rheumatol. 2016;68(7):1582-7
OA Knee Population Management
Projected growth in TKA United States from 2005 to 2030
Kurtz S. et.al. J Bone Joint Surg 2007:89:780-785
Surgery - TKA - UKA
Knee Osteoarthritis
Knee Osteoarthritis
Knee Osteoarthritis
Acta Orthop. 2017 Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ
Knee Osteoarthritis
Sellam. Nature Reviews Rheumatology Volume: 6 issue 11 (2010)
Nat Rev Rheumatol. 2011 Jan;7(1):13-22. doi: 10.1038/nrrheum.2010.178. Epub 2010 Nov 16. Pharmacologic therapy for osteoarthritis--the era of disease modification. Hunter DJ1.
Biologic treatments
• Any substance derived from animal products or other biological sources and used to treat or prevent disease
Bios (Life)
Symptoms modifying and/or Structure modifying?
Biologic treatments Tissue engineering
strategies
Tissue engineering strategies Biologic treatments
Cells
Scaffold
Signaling
Molecules
A
B 4
2 1
3
C
JBJS 86A:1541-1558, 2004
Cartilage Stem Cell Populations?
• Activation • Attachment • Proliferation • Migration • Differentiation • Survival • Self Renewal
• What cells do we want? • How can they assayed? • Where are they? • How many are there? Patient Variation • Harvest Technique? Yield? • Transplantation Environment? • Processing/Selection Methods? • Transplantation Method? • Clinical Setting of Need? • Preclinical Testing – Safety and Efficacy? • Regulatory Barriers – Uncertainty? • Market Size, IP Protection, Price? • Clinical Trials – Time/Money/ROI?
Questions – Problems - Opportunity
• What cells do we want? • How can they assayed? • Where are they? • How many are there? Patient Variation • Harvest Technique? Yield? • Transplantation Environment? • Processing/Selection Methods? • Transplantation Method? • Clinical Setting of Need? • Preclinical Testing – Safety and Efficacy? • Regulatory Barriers – Uncertainty? • Market Size, IP Protection, Price? • Clinical Trials – Time/Money/ROI?
Questions – Problems - Opportunity
Osteogenic CFUs
Chondrogenic CFUs
Fibroblasts/Endothelial Cells
Hematopoietic CFUs
Keratinocytes/Melanocytes
Osteoarthritis – Early Changes
2017
50 patients: 100 samples – Idiopathic Knee OA
Acta Orthop. 2017 Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ
Osteoarthritis – Early Changes
Varied Mechanisms
Acta Orthop. 2017 Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ
Osteoarthritis – Early Changes
Acta Orthop. 2017 Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ
Osteoarthritis – Early Changes
Acta Orthop. 2017 Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ
Osteoarthritis – Early Changes
CTP-C Assay Development CTP-C Assay Development
Proteoglycan Synthesis
Variation Between Cell Colonies
CTP-C Assay Development
AO = Acridine Orange
Time Lapse video - CTP-C heterogeneity
Colony type A Colony type B
A B C
A) Maximum intensity projection of live cell phase contrast image at Day 7 B) Mitosis events in time series (grey level = time frame, yellow=founding cell, red outline=colony footprint), C) histogram of mitotic events this colony. C) A histogram of the frequency of mitotic events.
Dynamic Metrics of Colony Formation
Ed Kwee
Automated Colony Analysis Tools
Automated Colony Management Tools
Moving to Performance-Based Selection
Cell X Xvivo System Module
Cell X Xvivo System Module
Cartilage Health and Disease
Future Health?
OA Knee Biologic Therapy
Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation
Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition?
Inhibit Chondrocyte Loss
Inhibit Subchondral Erosion
OA Knee Biologic Therapy
Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation
Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition?
Inhibit Chondrocyte Loss
Inhibit Subchondral Erosion
OA Knee Biologic Therapy
Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation
Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition?
Inhibit Chondrocyte Loss
Inhibit Subchondral Erosion
OA Knee Biologic Therapy
Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation
Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition?
Inhibit Chondrocyte Loss
Inhibit Subchondral Erosion
Cell Therapy Questions
Mechanisms
Degenerative
Trauma
Mechanical
Metabolic
Inflammatory
Toxic
Genetic
Osteoarthritis
Demographics
Traditional Therapies
Biologic Therapies
Cartilage Kinetics
Variation in Human OA
Cell Sources Targets
Osteoarthritis Overview Therapy
Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, …) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, iPS Genetic Modification
Sellam. Nature Reviews Rheumatology Volume: 6 issue 11 (2010)
Osteoarthritis Mechanisms
Osteoarthritis Overview Therapy
Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, …) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, iPS Genetic Modification
Symptoms modifying
Structure modifying
Steroids NSAIDS Other Anti-inflammatorys Hyaluronan IRAP
Osteoarthritis – Injectable Therapies
Cochrane 2015
• 27 Trials • 1767 participants
1-2 weeks
4-6 weeks
3 months
6 months
Nat Rev Rheumatol. 2018 Feb;14(2):73-74. doi: 10.1038/nrrheum.2017.219. Epub 2018 Jan 11. Osteoarthritis in 2017: Latest advances in the management of knee OA. McAlindon TE1, Bannuru RR1.
Normal Knee
Knee Osteoarthritis
Knee Osteoarthritis Decreased in hyaluronan
• Degradation • Reduced production • Increased clearance
Moreland LW. Arthritis Res Ther. 2003 Greenwald RA. Semin Arthritis rheum. 1991
• Normal healthy adult knees 2mL of synovial fluid • 0.5 to 4 mg/mL of Hyaluronan produced by type-B synoviocytes, fibroblasts mean molecular weight 5 x 106 Da
Why?
Balazs EA et al. Arhtritis Rheum 1967 Moreland LW Arthritis Res Ther 2003
• Viscoelastic shock absorber during high shear • Lubricant during slow movement • Chondroprotective • Anti-inflammatory • Other
HA Functions
HA concentration Molecular mass Viscosity of the synovial fluid
Exogenous intra-articular hyaluronan injections
• Peyron and Balazs (1974) Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints
Pathol Biol (Paris). 1974 Oct;22(8):731-6 J Rheumatol Suppl. 1993;39:3-9
“visco-supplementation”
HA concentration Molecular mass Viscosity of the synovial fluid
Knee OA
Joint lubrication by restoring or supplementing synovial fluid viscoelasticity
Approved as a biologic device for use in humans in Canada in 1992, and in the United States in 1997
55 NEJM 372;11 - March 12, 2015
56 JBJS 2016;98:1429-35
57
JBJS 2016;98:1429-35
58
JBJS 2016;98:1429-35
59
JAMA Internal Medicine October 2014 Vol. 174, 10
TODAY Multiple available commercial products
Johal H. et al. JBJS 2016;4(4) April 2016
Variation in:
• Molecular weight • Method of production • Half-life • Dosing regimen • Cost • …
Multiple available commercial products
American Journal of Sports Medicine, Vol. 44, No. 8 - 2015
• Molecular weight > 3000 kDa favorable efficacy results than MW < 3000 kDa
• Biological fermentation derived HA lower adverse events than Avian-derived HA
Knee Osteoarthritis
European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)
The use of IA HA in knee OA patients with mild–moderate disease, and for more severe patients wishing to delay TKR surgery, is
recommended
Impact Factor 3.9
Knee Osteoarthritis
Knee Osteoarthritis
65
CONCLUSION: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events.
Ann Intern Med. 2012 Aug 7;157(3):180-91. Impact Factor 16.5
JBJS APRIL 2016 · VOLUME 4, ISSUE 4
Heterogeneous trials with conflicting conclusions
- Unclear and discordant recommendations - Evidence favors clinically important reductions in pain and is safe in patients with knee OA
JBJS APRIL 2016 · VOLUME 4, ISSUE 4
HA injection in Knee Osteoarthritis
• HA injections for knee osteoarthritis provides a probable pain reduction and improvement of physical function
• Low-risk of harm • It is a viable option in younger patients with less severe
disease
Based on the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach:
Symptoms modifying
Structure modifying
Osteoarthritis – Injectable Therapies
Cells Proliferation Retention
ECM Formation Retention
Osteoarthritis Overview
Growth Cells Collagen GAG Vascularity
Structure
Remodeling (Homeostasis) Cells Collagen GAG Vascularity
Degradation Cells Collagen GAG Vascularity
Osteoarthritis Overview
Growth Cells Collagen GAG Vascularity
Structure
Remodeling (Homeostasis) Cells Collagen GAG Vascularity
Degradation Cells Collagen GAG Vascularity
Osteoarthritis Overview
Growth Cells Collagen GAG Vascularity
Mechanism Therapy Structure
Remodeling (Homeostasis) Cells Collagen GAG Vascularity
Degenerative
Trauma
Mechanical
Metabolic
Inflammatory
Toxic
Genetic
Degradation Cells Collagen GAG Vascularity
Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, …) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, iPS Genetic Modification
Osteoarthritis Overview Therapy
Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, …) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, iPS Genetic Modification
Late 1800 - Osteochondral Allografts
1980s – Microfracture
1990s – Mosaicplasty and OATS
1997 – Autologous Chondrocyte (ACI)
2007 – Juvenile Cartilage (DeNovo NT, ISTO)
2017 – Membrane ACI (MACI)
Cartilage Replacement Biologics Grade IV and Osteochondral Defects
Symptoms modifying
Structure modifying
Wnt Inhibitors A2 Microglobulin Toll-like receptors (TLR) 4 modulators TGF-B
Osteoarthritis – Injectable Therapies
Nat Rev Rheumatol. 2018 Feb;14(2):73-74. doi: 10.1038/nrrheum.2017.219. Epub 2018 Jan 11. Osteoarthritis in 2017: Latest advances in the management of knee OA. McAlindon TE1, Bannuru RR1.
Alpha 2 Macroglobulin (A2M) plasma protease inhibitor inhibits activities of ADAMTS-4,-5,-7, -12 , MMP-13 activity
Nat Rev Rheumatol. 2015 Mar;11(3):159-70. doi: 10.1038/nrrheum.2014.209. Epub 2014 Dec 16. TLR4 signalling in osteoarthritis--finding targets for candidate DMOADs. Gómez R1, Villalvilla A2, Largo R2, Gualillo O3, Herrero-Beaumont G2.
Toll-like receptors (TLR) 4 signaling in OA TLR4-regulating drugs could act as potential disease-modifying OA drugs
Allogeneic human chondrocytes transduced with a viral vector containing the gene for TGF-b1 transcription
Allogeneic human chondrocytes transduced with a viral vector containing the gene for TGF-b1 transcription
Nat Rev Rheumatol. 2011 Jan;7(1):13-22. doi: 10.1038/nrrheum.2010.178. Epub 2010 Nov 16. Pharmacologic therapy for osteoarthritis--the era of disease modification. Hunter DJ1.
Osteoarthritis Biologic Therapies
Osteoarthritis Overview
Growth Cells Collagen GAG Vascularity
Mechanism Therapy Structure
Remodeling (Homeostasis) Cells Collagen GAG Vascularity
Degenerative
Trauma
Mechanical
Metabolic
Inflammatory
Toxic
Genetic
Degradation Cells Collagen GAG Vascularity
Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, …) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, iPS Genetic Modification
- Few Safety Concerns - Poor Low level of Evidence
- (only 6 of 420 articles useful for efficacy comparison) - High risk of publication bias
2017
2016
Recent Systematic Reviews
Platelet Rich Plasma Knee OA
Campbell K et al. Arthroscopy 2016, Meheux C. et al. Arthroscopy 2016, Laudry A. et al. BJSM 2015, Riboh J. et al AJMS 2015
Sadabad H. et al. EP 2015 Lai L. et al. IJCEM 2015
1) Safe 1) Transient local adverse events such as pain or swelling,
for 2 or 3 days (<5%) 1) Improves pain and function for up to 12 to 24 months… 1) Low leukocyte concentration (LP-PRP)
Platelet Rich Plasma Knee OA
Campbell K et al. Arthroscopy 2016, Meheux C. et al. Arthroscopy 2016, Laudry A. et al. BJSM 2015, Riboh J. et al AJMS 2015
Sadabad H. et al. EP 2015 Lai L. et al. IJCEM 2015
Support
NIH - NIAMS
Team
Maha Qadan
Cynthia Boehm
Ed Kwee Venkata Mantripragada
Terri Zachos
Viviane Luangphakdy
Alan Sumski Selvam Selvaanish
Nicholas Piuzzi Eben Alsberg
Bob Sah
Veronique Lefebvre Ron Midura
Vince Hascall
The Cleveland Clinic Foundation
THANK YOU