Page 369 - Advances in Biomechanics and Tissue Regeneration

366 18. CARTILAGE REGENERATION AND TISSUE ENGINEERING

• Upper superficial or tangential zone (SZ): This zone, in contact with the synovial cavity, is thin and contains small
flattened chondrocytes surrounded by an ECM featuring abundant type II collagen fibrils arranged in parallel to the
surface, with lower levels of proteoglycans and keratan sulfate GAGs than the deeper zones.
• Intermediate or transitional zone (TZ): This zone contains round chondrocytes that are apparently randomly
distributed and collagen fibrils arranged obliquely to the surface and the highest levels of proteoglycans.
• Radial or deep zone (RZ): This zone occupies the greatest area; short columns of round large chondrocytes are arrayed
perpendicular to the surface, together with collagen fibrils that parallel the chondrocyte columns.
• Calcified zone (CZ): This zone contains a partly mineralized matrix and smaller chondrocytes and serves as the
transition zone between cartilage and underlying subchondral bone.
• Tidemark: This is a heavily calcified undulating line marking the transition between the noncalcified radial zone and
the calcified zone.
Articular cartilage exhibits crucial, diverse biomechanical functions in synovial joints, absorbing and distributing
loads to the opposing bony shafts, thus allowing frictionless movement [6]. Articular chondrocytes require specific
balancing of mechanical loads, potentially differing within each of the four layers; Chen et al. [3] showed that biome-
chanical stimulation in vitro was required to sustain functional tissue-specific cell populations. Although mature chon-
drocytes exhibit few mitoses, Muiños-Lopez et al. [5] reported that biopsies of the superficial and deep zones of
articular cartilage exhibited proliferative and chondrogenic potential, particularly of deep zone chondrocytes.
A subpopulation of slow-cycling cells has been identified on the surface of articular cartilage [21].
Apart from hyaline articular cartilage, the capsule, and synovial fluid, some synovial joints contain additional struc-
tures such as menisci, tendons, or ligaments that improve mobility and function.

18.1.4 Cartilage ECM Turnover [2, 10]

Cartilage ECM undergoes continuous internal remodeling throughout life since cells replace degraded matrix com-
ponents. Normal matrix turnover requires that chondrocytes detect changes in matrix composition and respond by
synthesizing appropriate new molecules; chondrocytes are thus engaged in continual matrix turnover [19]. Stimuli
(such as pressure) applied to articular cartilage create mechanical, electrical, and chemical signals directing chondro-
cyte synthetic activities. However, as the body ages, chondrocytes lose the ability to respond to such stimuli, and the
matrix composition changes gradually.
Constant turnover of ECM molecules throughout life is required for tissue repair. However, renewal of mature artic-
ular cartilage is very slow because certain ECM components such as the collagen network are very stable, exhibiting
negligible turnover after adolescence [22]. Matrix molecules are degraded by matrix metalloproteinases (MMPs)
2+
2+
(Zn -orCa -dependent enzymes secreted by chondrocytes but present at only low levels in healthy articular car-
tilage). The MMPs include a collagenase that specifically degrades ECM collagen fibrils, allowing cells to expand, to
become repositioned within growing isogenous groups. The aggrecan and HA turnover rates are similar [19]; both are
continuously synthesized by cartilage and have half-lives of the order of weeks reflecting, in part, endocytosis by chon-
drocytes. Knudson et al. [19] showed that cleavage of aggrecan and further degradation to a threshold size were
required for HA internalization. Both proteoglycan synthesis and breakdown decrease with increasing age [23].
The primary role of articular cartilage is load transmission/distribution; mechanical loading influences cartilage
composition. The reduced mechanical load in paraplegic patients diminished articular cartilage thickness over 1year;
a lack of mechanical stimulation caused atrophy, with formation of thinner and softer cartilage that was more suscep-
tible to trauma [23, 24].

18.2 ARTICULAR CARTILAGE AGING AND SENESCENCE

During aging, articular cartilage undergoes many changes in molecular structure in terms of ECM component levels
and qualities; the changes resemble those noted during degeneration associated with osteoarthritis. Anabolic activity
and water content fall, as does fibrillation, associated with fragmentation of core protein of aggrecan and chondroitin
sulfate GAGs, altered sulfation of GAG chains, and changes in cross-linking between collagen molecules of reduced
tensile strength and stiffness [9, 25]. Some changes of the articular surface and focal defects such as superficial fibril-
lation are common and are spontaneously repaired but tend to accumulate with age [14].

II. MECHANOBIOLOGY AND TISSUE REGENERATION