ARTICULAR CARTILAGE AND HEALING

BASIC SCIENCE

VASU NALLALUTHAN SPV: DR. BADRUL

Gross anatomy & Type of cartilage1

Cartilage elastic, fibro-cartilage, fibro-elastic and hyaline cartilage. Articular cartilage type of hyaline cartilage that cover gliding surfaces of synovial joint. Highly specialized tissue2 Unique mechanical behavior2 Poor regenerative capacities2

Embryology of Cartilage1
Cartilage arises from mesenchyme. Some mesenchyme cells aggregate to form a blastema (5/52 gestational age). The cells of blastema begin to secrete cartilage matrix chondroblasts. Further development
Extracellular matrix that produced gradually pushes the cells apart cells encased in tough and specialized matrix (chondrocytes) .

The mesenchymal tissue surround the blastema membrane perichondrium.

Anatomy of articular (Hyaline) Cartilage1

Aneural, avascular and alymphatic structure. Consists:
Chondrocytes Extracellular matrix ~ dense
primarily of water, collagen, and proteoglycan.

Low metabolic activity2 Chondrocytes

form only 15% volume of the articular cartilage. receive nutrition via diffusion through the matrix. very specialized cells responsible for synthesizing and maintaining the matrix infrastructure.

Anatomy of articular (Hyaline) Cartilage

Matrix pH is 7.4, changes can easily disrupt the highly specialized matrix infrastructure. Chondrocyte metabolism for the maintenance of a stable and abundant extracellular matrix. Mixture of fluid and matrix provides hyaline cartilage with viscoelastic and mechanical properties for efficient load distribution.

Composition of articular cartilage

Water1,2: 65 80%
80% superficial zone; 65% deep zones Allows load-dependent (hydraulic pressure) deformation of the cartilage. Viscoelastic properties2
Its time dependence, reversible deformability, and ability to dissipate load.

It provides nutrition and medium for lubrication, creating a lowfriction gliding surface. majority of water within the interstitial intrafibrillar space (by collagen proteoglycan solid matrix)2
Related to Donnar osmotic pressure fixed ve charges on proteoglycan

Composition of articular cartilage

Collagen1,2:
1020% of wet weight of the articular cartilage. triple helix structure Type II collagen forms the principal component (90 95%) of the macrofibrilar framework provides a tensile strength to the articular cartilage. In solid matrix collagen line up in staggered end-toend and side-to-side fashion to form fibrils with holes and overlaps. Intra-and intermolecular cross linking fibrils stabilize the matrix.

Composition of articular cartilage

Proteoglycans1,2: 1020% wet weight
protein polysaccharide molecules provide compressive strength to articular cartilage. Two major classes in articular cartilage
LARGE aggregating proteoglycan monomers or aggrecans SMALL proteoglycans including decorin, biglycan and fibromodulin. They are produced inside the chondrocytes and secreted in the matrix.

Composition of articular cartilage

Aggregan
long protein core with up to 100 chondroitin sulfate and 50 keratan sulfate glycoaminoglycan chains. Bind via a link protein on the protein core to a hyaluronate molecule.

Hyaluronate molecules form a backbone with palisading aggregan molecules macromolecular complex proteoglycan aggregate. The interaction between the proteoglycan molecules and collagen fibrils creates a fiber-reinforced composite solid matrix. The proteoglycans are entangled and compacted within the collagen interfibrillar space, which helps to maintain a porouspermeable solid matrix and determines the movement of the fluid phase of the matrix

Proteoglycan aggregate and aggrecan molecule2

Source: Bhosale AM and Richarson JB. (2008). Articular cartilage: structure, injuries and review of management. British Medical Bulletin; 87:77-95

Type of collagen and its f(x)2

Source: Bhosale AM and Richarson JB. (2008). Articular cartilage: structure, injuries and review of management. British Medical Bulletin; 87:77-95

Ultra-structure of articular cartilage1

Source: Bhosale AM and Richarson JB. (2008). Articular cartilage: structure, injuries and review of management. British Medical Bulletin; 87:77-95

Ultra-structure of articular cartilage1

Chondrocytes organize the collagen, proteoglycans and non-collagenous proteins unique and highly specialized tissue, suitable to carry out functions. Morphologically 4 named zones, from top to bottom
1. 2. 3. 4. Superficial zone Transitional zone Middle (radial) or deep zone and Calcified cartilage zone

Structure of Cartilage2

Articulating Surface (Superficial zone)1

The thinnest layer, composed of flattened ellipsoid cells. Lie parallel to the joint surface
The fibrils provide greatest tensile and resist shear strength2

Covered by a thin film of synovial fluid lamina splendens or lubricin.

Protein responsible for smooth gliding surface2 Chondrocytes synthesize high concentration of collagen + low concentration of proteoglycans highest water content zone.

Also as a filter for the large macromolecules protecting cartilage from synovial tissue immune system. Disruption of this zone alters the mechanical development of osteoarthritis. A.k.a tangential zone

Transitional zone1,2
Cell density lower, with predominantly spheroid-shaped cells, embedded in abundant extracellular matrix. Large diameter collagen fibres randomly arranged in this zone. Proteoglycan aggrecan concentration is higher in this zone.

Middle (radial)/ Deep zone1,2

40% to 60% of articular cartilage volume Higher compressive modulus than superficial zone Collagen fibrils are thicker fibers, packed loosely, and aligned obliquely to the surface. Chondrocytes are arranged perpendicular to the surface and are spheroidal in shape. Highest concentration of proteoglycans. The cell density is lowest in this zone.

Calcified cartilage zone1,2

Mineralized zone contains small volume of cells embedded in a calcified matrix a very low metabolic activity. Chondrocytes hypertrophic phenotype and synthesize Type X collagen, responsible for providing important structural integrity and provide a shock absorber along with the subchondral bone. The visible border between the 3rd and 4th zones is termed as tidemark, which has a special affinity for basic dyes, such as toluidine blue.
This zone provides an important transition to the less resilient subchondral bone. This zone was considered as an inactive zone Chondrocytes in this zone were able to incorporate sulphate into pericellular and territorial matrix. Following injury, the metabolic activity in this zone becomes temporarilyimpaired.

Matrix zones is organized in three different zones in the cartilage 1. Pericellular 2. Territorial 3. Inter-territorial

Calcified cartilage zone

Pericellular matrix :
Thin rim of matrix-organized issue in close contact with the cell membrane (2-m m wide). Rich in proteoglycans and non-collagenous proteins, like cell membrane-associated molecule anchorin CII, and decorin. Contains non-fibrillar collage, made of Type VI collagen. Surrounds pericellular region and is present throughout the cartilage. Surrounds individual chondrocytes or a cluster of chondrocytes including their pericellular matrix. In the radial zone, it surrounds each column of chondrocytes. Collagen fibrils organized in a criss-cross forming a fibrillar basket surrounding clustered bunch of chondrocytes, protecting them from mechanical impacts. Most of the volume of all types of matrices + largest diameter of collagen fibrils. Fibres oriented differently in different zones, depending on the requirement, viz. parallel in the superficial zone and perpendicular in the radial zone. Special features to identified formation of aggregates of proteoglycan molecules

Territorial matrix

Inter-territorial matrix

ORGANIZATION OF ARTICULAR CARTILAGE3

f(x) of hyaline articular cartilage1,2

1. Provides a low-friction gliding surface. 2. Acts as a shock absorber. 3. Minimizes peak pressures on the subchondral bone. 4. compressive strength 5. Wear-resistant under normal circumstances

f(x) of the matrix1

1. Protects the chondrocytes - mechanical loading, maintain their phenotype. 2. Storage cytokines and growth factors for chondrocytes. 3. Determines the type, concentration and rate of diffusion of the nutrients to chondrocytes. 4. Acts as a signal transducer for the cells.
Matrix deformation produces mechanical, electrical and chemical signals, affecting the functions of chondrocytes. Matrix recording a loading history of the articular cartilage.

Natural Hx of Chondral Injuries1

Articular cartilage lesions most commonly 4th decade of life Full thickness lesions common in young adults 3rd decades, following acute traumatic injuries. Repetitive minor trauma and major overt injuries Typical symptoms of chondral injury are similar to meniscus tear, like swelling, local pain, locking, pseudo-locking and catching. Outerbridge has classified these focal chondral defects into different stages, based on the severity of the defect. Large focal defects untreated premature endstage arthritis.

Natural Hx of Chondral Injuries

Structural lesion

Local Bleeding

Formation of blood clot

Localized spontaneous repair activity

Direct ossification @ bony surface

Sx & Symptom Articular Cartilage Lesion3

Generally do not heal, if heal only partially under certain biological conditions. Articular defects > 2-4 mm in diameter rarely heal even with such advances as the use of continuous passive motion Sx and Symptom:
Joint disability Joint pain, swelling, Locking phenomena Reduced or disturbed function. Joint degeneration if worsen

Believed to progress to severe forms of OA if untreated well

Partial thickness vs Full thickness

Partial
Damage to the cells and matrix components limited to superficial articular involvement. Characterized by proteoglycan (PG) concentration and hydration. in cartilage stiffness and an in hydraulic permeability leading to greater loads transmitted to the collagen-PG matrix, which increases ECM damage. Breakdown of the ECM may lead to greater force transmitted to the underlying bone that eventually leads to bone remodeling.

Full

By visible mechanical disruption limited to articular cartilage. Characterized as (but not limited to) chondral fissures, flaps, fractures, and chondrocyte damage. Lack of vascular integration, and lack of migration, of mesenchymal stem cells to the damaged area limits the repair of this type of injury. Mild repair occurs as chondrocytes start proliferating and synthesizing additional ECM Response is short lived, and defects remain only partially healed. Normal articular cartilage that is adjacent to the damaged site may undergo additional loading forces pre-disposing it to degeneration over time.

Partial thickness vs Full thickness

Classification3
OUTERBRIDGE CLASSIFICATION OF CHONDRAL INJURIES

MODIFIED INTERNATIONAL CARTILAGE REPAIR SOCIETY CLASSIFICATION SYSTEM FOR CHONDRAL INJURY

Management
The most commonly tx for end-stage knee osteoarthritis prosthetic replacement of the articular surface (a.k.a total knee arthroplasty).
Suitable for the elderly people (> than 60 years of age, with a sedentary life style) Pt < 45 years of age not ideal candidates for TKR

Repair & Regeneration of chondral Injuries1

Repair restoration of a damaged articular surface with a neocartilage tissue, which resembles to the native cartilage, but does not necessarily duplicate its structure, composition and function. Regeneration formation of tissue, indistinguishable from the native articular cartilage. A typical tissue response to injury follows a cascade of necrosis, inflammation, repair and scar remodelling. Vascular phase of this cascade is the most important determinant of healing. Hyaline cartilage, being avascular structure, lacks an ability to generate this vital response. Thus, after any mechanical insult or damage, the intrinsic reparative ability of cartilage is very low. Healing of the cartilage defect means restoring structural integrity and function of the damaged tissue.

Factors a/w repair response1

Depth Of Defect Size of Defect Age Trauma Mechanical malalignment of the joint

Intervention
Therapeutic interventions without active4
Lavage and Arthroscopy Shaving Laser Abrasion/ Laser Chondroplasty Bone marrow stimulation1
Joint Debridement and Pridie drilling1 Abrasion Chondroplasty4 Microfracture technique4 Spongialization4

Extensive Surgical intervention4,6

Osteotomy1 Distraction of Joint

Intervention
Therapeutic interventions with active biologics4
Mosaicplasty (Osteochondral Transplantation)1 Perichondrial grafts 1 Periosteal grafts 1 Autologous chondrocyte implantation1 Matrices Carbon fibre implants1 Cells in Suspension Cells in a Matrix-Carrier System

Tissue Engineering4

Intervention

Different strategies for cartilage repair

Osteochondral Transfer

Autologous Chondrocyte implantation

References
1. 2. 3. Bhosale AM and Richarson JB. (2008). Articular cartilage: structure, injuries and review of management. British Medical Bulletin; 87:77-95 Pearle AD et al., (2005) Basic Science of Articular Cartilage and Osteoarthritis. Clinical Sports Medicine; 24: 1-12 Pylawka TK et al. Chapter 30: Articular Cartilage Injuries. Available at www.pacificaorthopedics.org/downloads/knee/Articular_Cartilage_Injuri es.pdf. Accessed on 14 /06/12 Hunziker E.B., (2001).Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis and Cartilage 10, 432463. Redman et al. (2005) Current Strategies for Articular Cartilage Repair. Review of Cartilage Repair . Strategies European Cells and Materials Vol. 9: pp 23-32 ODriscoll SW. (1998) Current Concepts Review: The Healing and Regeneration of Articular Cartilage. Journal of Bone and Joint Surgery, Incorporated. Vol 80-A:1795 - 1812

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