Page 371 - Advances in Biomechanics and Tissue Regeneration

368 18. CARTILAGE REGENERATION AND TISSUE ENGINEERING

without visible collagen loss, followed by collagen loss and, finally, irreversible destruction [41]. In vitro, mechanical
stress accelerated chondrocyte senescence via increased oxidative stress, damaging mitochondria and triggering either
apoptosis or senescence, thus reducing the number of functional chondrocytes [29, 35].
Although mature chondrocytes exhibit little mitotic activity, a subpopulation of slow-cycling cells in the superficial
zone exhibited increased proliferation and rearrangement at the onset of osteoarthritis, contributing to cartilage repair
under pathological conditions [21, 42]. Seol et al. [43] reported that chondrogenic progenitor cells of the superficial
zone could migrate to damaged areas and proliferate therein to cover damaged cartilage with a continuous coat of
lubricin; the cells were thus involved in the early stages of cartilage repair.
During osteoarthritis development, chondrocytes undergo many phenotypic changes, often influenced by aging,
including changes in responses to external stimuli promoting abnormal ECM remodeling [14]. Chondrocytes secrete
increased levels of many inflammatory cytokines, growth factors, and other factors that are together termed the
senescence-messaging secretome [44], which suggests that cell senescence may play a pathological role in osteoarthritis
[26]. One such factor is vascular endothelial growth factor (VEGF), a signaling protein promoting blood vessel forma-
tion, which may contribute to dysregulated osteogenesis and osteophyte formation. Matrix-degrading proteases
induced by proinflammatory cytokines also increase in level; these degrade type II collagen lattices. Other changes
include telomere attrition, activation of the DNA damage response, and secretion of reactive oxygen species [26]. Oxi-
dative stress is a major contributor to cartilage breakdown in osteoarthritis and age-associated disease [45]; advanced
oxidation protein products have been detected in the synovial fluid and plasma of osteoarthritis patients and used as
biomarkers of disease progression [46].
Articular chondrocytes are responsible for the secretion and turnover of ECM components and are crucial in terms
of ECM homeostasis; in osteoarthritis, the balance between synthesis and degradation of matrix components shifts in
favor of catabolic events, thus promoting pathological tissue remodeling and, eventually, breakdown [14, 47]. As the
articular cartilage is destroyed in osteoarthritis, its ECM components (such as type II collagen and proteoglycan) are
degraded [13]; the pronounced loss of aggrecan observed in osteoarthritis causes a dramatic increase in tissue hydrau-
lic permeability [6].
The PCM surrounding chondrocytes plays an important role in joint protection from osteoarthritis. The lack of one
or more PCM components disrupts matrix structure; the chondrocytes are then less protected from mechanical stress
and more exposed to molecules from the territorial and interterritorial matrices (which would normally not be encoun-
tered). In particular, when type II collagen binds to chondrocyte membranes, it activates the tyrosine kinase receptor
and its intracellular signaling pathway, in turn inducing expression of MMPs that degrade type II collagen and pro-
teoglycans, thus advancing osteoarthritis [13].
Currently, no pharmacological therapy effectively treats osteoarthritis, preventing or reversing progressive joint
damage in most patients. The only therapeutic approaches are pain management and joint replacement in the most
severe cases; new treatments are required.

18.4 ARTICULAR CARTILAGE AND TISSUE ENGINEERING

Various surgical methods including subchondral drilling, microfracture, or nanofracture have often failed to trigger
functional hyaline cartilage regeneration [48]; in this context, tissue engineering seems to be promising in terms of
repairing, regenerating, and/or enhancing movement of arthritic joints [14]. The first efforts in this area were made
in the 1970s when Green [49] transplanted rabbit chondrocytes were grown ex vivo into cartilage defects (allografts). In
1994 cartilage tissue engineering was tested in patients with deep cartilage defects of the knee; healthy chondrocytes
from the same patients were isolated, cultured, and injected into the affected areas, and the results were promising [50].
In the time since these early attempts, tissue engineering has sought to create articular cartilage as similar as possible to
native tissue, using different approaches involving, principally, three components: cells that can differentiate into
chondrocytes and maintain the chondrocyte phenotype, scaffolds providing adequate 3-D environments, and growth
factors inducing cell growth and differentiation (Fig. 18.5).

18.4.1 Cells

Various sources of cells generating neocartilage in both scaffold-free and scaffold-based systems are available. Such
cells must be readily accessible and exhibit high proliferative rates and stable phenotypes. Regenerated cartilage must
be rich in type II collagen and aggrecan, nonimmunogenic, and nontumorigenic [51]. Thus the most obvious cell source

II. MECHANOBIOLOGY AND TISSUE REGENERATION