Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com1
Dr.Sandeep Agrawal, Agrasen Hospital,
Gondia Maharashtra
India [email protected]
www.agrasenortho.com
Articular Cartilage :Repair To Regenerate To Replace
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com2
Regenerate Identify the cues that allow for regeneration without scarring Like growing a new limb Repair Stimulate the tissue at a cell or molecular level, even at level of DNA, to repair itself. Replace A biological substitute is created in the lab that can be implanted to replace the tissue or organ of interest
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Regenerate, repair and replace
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!!• Biodegradable Scaffolds to !
anchor, deliver and orient cells!!
• Bioactive factors (Reagents) to !provide instructional cues to cells!!
• Cells: responsive to their !environment therefore milieux shape/ O2 Tension effects should be considered to optimize growth
Ultimate goal:Cells
Scaffold Reagents
3 Key Requirements
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● Restore smooth articular cartilage surface!
● Relieve patient symptoms and improve function !
● Match biomechanical/biochemical properties of normal hyaline cartilage!
● Prevent or slow progression of focal chondral injury to end- stage arthritis
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Goals of Cartilage Repair
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Autologous Chondrocyte ImplantationDebridement & Lavage Microfracture Osteochondral Grafting
Palliative Reparative Restorative
CLINICAL
UTILITY
Treatment Options for the Cartilage Bio-surgeon in 2009
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Autologous Chondrocyte Implantation (ACI)
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Attempts to regenerate articular cartilage have been introduce in clinical practice with autologous chondrocytes implantation (ACI)
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com99
Autologous Chondrocyte Implantation (ACI)
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Autologous MSCs were expanded ex vitro, embedded in a collagen gel and re-implanted into areas of articular cartilage defect in osteoarthritis patients. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage 2002;10:199-206.
MSCs in cartilage repair
Take healthy cartilage tissue Tissue culture of isolated chondrocytes Inject the cultured chondrocytes in knee under patch Treat chondral defects
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▪ Strengths:!▫ Can produce hyaline-like cartilage !▫ Not limited by defect size!▫ Most commonly used for
moderate-to-large defects in patients who have failed previous interventions !
▫ 15 year hx of clinical use !▫ > 80 citations in literature!
▪ Limitations:!▫ Open/More invasive!▫ Expensive!▫ Longer recovery period!▫ 2 stage procedure!▫ Ultrastructurally still not true
articular cartilage13
Autologous Chondrocyte Implantation : ACI
1. .
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!
●Autogenous cells!●Seeded scaffold or liquid gel!●Minimizes periosteal
related complications !●Allows arthroscopic implant
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2nd Generation Cell Therapies
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●Autogenous!●Allogeneic!●3-D Cartilage graft!●Technical ease might allow ! arthroscopic insertion with! bioadhesive
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3rd Generation Cell Based
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● Middle architectural zone called “the netting” is made of aggregates of proteoglycans called glycosamino- glycans (GAG’s): This netting holds water i.e.: gives this zone its hydrophilic character that yields the low friction, fluid wave enabling smooth joint motion
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Unique building block of articular cartilage matrix is Type II collagen
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com17
● Growth Factors: ! -IGF-1, FGF, TG-Beta super family!Can we stimulate these to increase GAG synthesis after
cartilage injury !!
● Catabolic Factors: Cytokines: ! - IL-1, TNF, IL-6,7,8!Can we inhibit these to avoid matrix breakdown after cartilage
injury!
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Other Synovial Fluid Factors:
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● Lesion ≥ 2 cm2
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Treatment Decision Algorithm
Lesion < 2 cm2
Secondary Treatment
▪ D & L ▪MST
▪Osteochondral Autograft
▪ ACI ▪Osteochondral
Autograft
Primary Treatment
Secondary Treatment
Primary Treatment
▪ ACI ▪Osteochondral
alloGrafting
Low Demand
High Demand
▪ D & L ▪MST ▪Osteochondral
Grafting
▪Osteochondral alloGrafting
Special Issues exist for the competitive Athlete? It is always about time and timing!
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BMAC FOR CARTILAGE REPAIRBMAC FOR CARTILAGE REPAIR
21Wednesday, 4 June 14
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Osteochondral Lesions of the Knee
Osteochondral Lesions of the Knee: A New One-Step Repair Technique with Bone-Marrow-Derived Cells. By Roberto Buda, MD, Francesca Vannini, MD, PhD, Marco Cavallo, MD, Brunella Grigolo, PhD, Annarita Cenacchi, MD, and Sandro Giannini, MD J Bone Joint Surg Am. 2010;92 Suppl 2:2-11 d doi:10.2106/JBJS.J.00813
Mesenchymal stem cells represent 2% to 3% of the total mononuclear cells in bone marrow and have the ability to differentiate into various lineages, including osteoblasts and chondroblasts. The rationale of the ‘‘one-step technique’’ is based on the idea of transplanting the entire bone-marrow cellular pool instead of isolated and expanded mesenchymal stem Cells.
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com2323
Microfracture● Strengths:!
● Arthroscopic procedure is relatively simple/reproducible!
● Inexpensive!● Long history of clinical use!(> 28 studies w/ 6 RCT’s in lit.)!
● Limitations:!● Creates fibrocartilage/
poor wear characteristics!
● More effective on smaller defect (< 4 cm2)!
● 6–8 weeks protected- wt. bearing and CPM required
Courtesy of Brian J. Cole, MD
1. St 2. Knee. A Randomized Trial. J of Bone Joint Surg. 2004;86-A:455-464.
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com2424
Microfracture has been a good step ….but not ideal: not truly restorative
● good 2 yr clinical effect with waning clinical effect in larger lesions!
● "osteochondral" perforating the subchondral bone plate/tidemark!
● moving up of the bone front leading to intralesional osteophytes!
● Over time deterioration of the repair tissue!● Declination of function and athletic activity!Mithoefer: JBJS Am 2005; 87 (9) 1911-20 !Buckwalter, Grodzinsky: Articular cartilage and osteoarthritis: Instr. Course Lect 2005; 54:
465-80!Minas; Orthopedics 1997; 20 (6) 525-38!Kreuz: Osteoarthritis and Cartilage (2006) 14, 1119-1125 !Kreuz: The Journal of Arthroscopic and Related Surgery Vol 22, No 11(November) 2006,
1180-1186 !Brown : Clin Orthop Relat Res 2004; 422: 214-23!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com2626
Osteochondral Autograft● Strengths:!
● May be performed arthroscopically/open !
● Fills defect with native cartilage!
● Limitations:!● Limited to smaller defects !● Donor site morbidity !● No lateral integration!● Congruity of joint difficult
to reproduce with multiple plugs Courtesy of Brian J. Cole, MD
1. Levy, A.S. Osteochondral Autograft ofr the Treatment of Focal Cartilage Lesions. Operative Techniques in Orthopedics. Management of Chondral Injury: Perspectives in the Millennium. 2001;11:108-114. 2. Levy, A.S. and Meire, S.W. Osteochondral Autograft Replacement. In: Cole, B.J. and Malek, M.M. Articular Cartilage Lesions. Practical Guide to Assessment and Treatment. New York, New York: Springer, ; 2004:73-81.
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com2727
Osteochondral Allograft● Strengths:!
● Bone fixation!
● Hyaline cartilage!
● Fresh Allografts have excellent long term results (Garrett/ Gross)!
● Limitations:!● Limited supply!
● Disease transmission !● ( partially mitigated by cold
storage: 20 days)!
● ?Viability of chondrocytes !● appx. 20 % Non-union
Courtesy of Brian J. Cole, MD
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com2929
ADS/ MSC in osteoarthritis • Desando and co-workers report in Arthritis Research
& Therapy that intra-articular delivery of adipose-derived stem cells attenuates progression of synovial activation and joint destruction in Osteoarthritis.
• Mesenchymal stem cell therapy in osteoarthritis:
advanced tissue repair or intervention with smouldering synovial activation
• Peter LEM van Lent* and Wim B van den Arthritis Research & Therapy 2013, 15:112 http://arthritis-research.com/content/15/2/112
Cartilage is avascular tissue with low number of cells with poor proliferation capacity. !Damaged cartilage does not self-regenerate and is a major cause of joint disease i.e. osteoarthritis. !
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com30
Mesenchymal stem cells in arthritic diseases
MSCs possess potent immunosuppression and anti-inflammation effects through secretion of various soluble factors, MSCs can influence the local tissue environment and exert protective effects with an end result of effectively stimulating regeneration in situ. Can be used for therapeutic application in degenerative joint diseases such as RA and OA. Faye H Chen and Rocky S Tuan Arthritis Research & Therapy 2008, 10:223 (doi:10.1186/ar2514)
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com31
■ Mimic usual cartilage environment – Cartilage cells – Collagenous scaffold – Doesn’t require extensive
blood supply31
Replacement cartilage
A close up image of cells in the replacement cartilage
The challenge is to engineer cartilage that is biochemically, structurally and biomechanically similar to normal cartilage
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“Future belongs to those who are willing to work for it and the best way to Predict Future is to create it.”
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