Cartilage Regeneration: A challenge in OA KNEE

Dr Vaibhav Bagaria MBBS MS FCPS

Arthroplasty & Sports Surgeon: CARE hosp & ORIGYN, NagpurVisiting Arthroplasty Surgeon: Apollo Hospital, Noida &

Columbia Asia Hospital, GZB

A ‘Good Start’ Dr Jain ?

To recreate what God has created?

CAD 2012Mumbai,India

Cartilage regeneration In ‘Arthroplasty’ Meeting

Cartilage consists of cells called chondrocytes and extensive extracellular matrix rich in glycoaminoglycans, proteoglycans and collagens.

3 forms of cartilage • hyaline cartilage (articular joints, type 2 collagen)• fibrocartilage (meniscus, intervertebral discs,

type 1 collagen)• elastic cartilage

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.

Cartilage

The challenge is to engineer cartilage that is biochemically, structurally and biomechanically similar to normal cartilage

• Bioactive factors• Extracellular matrix• Scaffold/delivery system• Mechanical stimulation• Genetic manipulation

Cells

Scaffold

Growth factor/peptide

Efficient cartilage repair

site/tissue specific cartilage

OA KNEECartilage damage in osteoarthritis is widespread

and lesions are large

Mechanical abnormalities -> cause localized regions of dynamic loading stress

local environment -> presence of signals which promote inflammation, suppress cartilage matrix synthesis and enhance matrix degradation.

Paradoxically, endogenous stem-cell like progenitor cells with chondrogenic potential found which is not present in normal cartilage

Cellular based therapy

Adult Chondrocyte

Adult Mesenchymal Stem cell

Human Embryonic Stem Cell

Inducible Progenitor stem cell

Adult chondrocyte based therapy

A preventative strategy to repair articular cartilage damage following acute injury

Using cartilage grafts or implanted chondrocytes to replace focally damaged lesions

limited to repair of localized articular cartilage injury in healthy and relatively young patients not for the typical OA with more widespread damage.

OATS -> ACI -> MACI -> HACI (hyaluronan scaffold) -> CCI ( characterized by chondrogenic markers)

Cartilage repair FIRST GEN

Since its introduction, ACI has become a widely applied surgical method with good to excellent clinical outcomes.

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

Brittberg M et al (1994) N. Engl J Med

Cell expansion

> 70% cases of repair

intestinal

skin

blood

beta cell

mesenchymal

liver

retinal

neural

indefinite self renewal

differentiation

stem cellll

limited self renewal

progenitoritor cell

Stem cells

amniotic hES testicular

Pluripotent: Embryonic Stem Cells (ESCs), Induced Pluripotent Stem Cells (iPSCs)

Multipotent: Adult Stem Cells, e.g. Bone marrow derived Stem Cells (BMSCs), Fat-derived Stem Cells (ADSCs), others

Stem Cells

Adult Mesenchymal stem cell based therapyMesenchymal Stem Cells (MSC) can be obtained

from bone marrow, synovium, fat, or umbilical cord.

Distinct potential for differentiation into the chondrogenic lineage.

Adipocyte-derived MSC have been suggested to be most chondrogenic

May be differentiated into chondrocytes using growth factors such as (BMP) (IGF) (FGF], or using scaffolds [40] which may release pro-chondrogenic signals such as TGF-β

Source of Stem Cell

Fat (AMSC) or Bone Marrow (BMSC) ?

www.abcam.com

mesenchymal stem cell

Bone marrow

Principles of Chondrogenesis

2mm burr/drill

Depth 5 to 10mm

1 to 2mm gaps

Light burring in between drill holes

Correct mal-alignment

Treat associated injuries

AMSC + Matrix

Intra-articular injections

CPM

Rehab protocol

Technique

Bone Marrow Aspiration

ConcentrationSeeding

Arthroscopy

Adapted from Dr Khay-Yong SAW, KLSMC

Dri

lling

Dri

lling

Dri

lling

Dri

lling

Dri

lling

Dri

lling

Blood clot scaffold

References:

hESC- Human Embryonic Stem CellsLimitless no. of cell with chondrogenic potential.

Protocols have been defied; most commonly using BMP, involve an intermediate stage – Embryoid body formation.

Encouraging results in vivo in rat and other animal models.

Safety: ? Teratoma, Xenogenic contamination, Immune rejection( caritlage immune privileged site).

Ethical issues loom large! Toh WS, Lee EH, Guo XM, Chan JK, Yeow CH, et al. (2010)

Cartilage repair using hyaluronan hydrogel-encapsulated human

embryonic stem cell-derived chondrogenic cells. Biomaterials 31:

6968-6980.

Gong G, Ferrari D, Dealy CN, Kosher RA (2010) Direct and

progressive differentiation of human embryonic stem cells into

the chondrogenic lineage. J Cell Physiol 224: 664-671.

iPSC – Inducible Progenitor stem cells pluripotent stem cells derived from somatic

cells

a compelling alternative to allogenic cell

readily available from sources such as adult skin

can provide patient-specific cell-mediated therapy

Development of procedures to induce pluripotency of the somatic cells, without modification of the cellular genome

iPSC – Inducible Progenitor stem cellsstandard methodology for induction of

pluripotency in iPSC involves viral transduction using transcription factors including oncogenes

insertional mutagenesis and increased risk of tumor formation

Methodology for generation of iPSC is rapidly evolving, and reprogramming of adult somatic cells is now being demonstrated which avoids permanent transgene integration, using excisable plasmids.

CONCLUSIONOsteoarthritis is present in epidemic proportions

in this country and around the world

Cell-based repair strategies are among the most promising of the available approaches

A critical barrier to success in cell-based articular cartilage repair is identification of a readily available exogenous source of cells with the ability to seamlessly repair articular cartilage damage and restore long-term joint function.

Yet… the future is out there in these tiny little invisible things…

We must welcome the

Future,

remembering

that soon it will be the Past;

we must respect the Past,

remembering that once it

was

all that was humanly

possible.

Thanks !