orthobiologics of articular cartilage:repair to regenerate to replace dr.sandeep c agrawal agrasen...

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

mailto:[email protected]

http://www.agrasenortho.com


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


!!• 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


● 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


Autologous Chondrocyte Implantation (ACI)


Attempts to regenerate articular cartilage have been introduce in clinical practice with autologous chondrocytes implantation (ACI)


Autologous Chondrocyte Implantation (ACI)


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Surgical Technique


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


▪ 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. .


!

●Autogenous cells!●Seeded scaffold or liquid gel!●Minimizes periosteal

related complications !●Allows arthroscopic implant

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2nd Generation Cell Therapies


●Autogenous!●Allogeneic!●3-D Cartilage graft!●Technical ease might allow ! arthroscopic insertion with! bioadhesive

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3rd Generation Cell Based


● 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


● 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:


● 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


Marrow aspiration


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.


Microfracture Technique


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.


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!


Osteochondral Graft


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.


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


Arthritic Diseases


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. !


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)


■ 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


“Future belongs to those who are willing to work for it and the best way to Predict Future is to create it.”

This presentation is for orthopaedic doctors and students in general. . Some graphics and jpeg files are taken from Google and yahoo

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[email protected] for prompt deletion. • It is intended for use only by the doctors of orthopaedic surgery.

. Views expressed in this presentation are personal. • .For any confusion please contact the sole author for clarification.

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[email protected] www.agrasenortho.com

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orthobiologics of articular cartilage:repair to regenerate to replace dr.sandeep c agrawal agrasen...

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