Page 374 - Advances in Biomechanics and Tissue Regeneration

18.4 ARTICULAR CARTILAGE AND TISSUE ENGINEERING 371

a 3-D environment with specific chondrogenic factors including TGF-β1, insulin-like growth factor-1 (IGF-1), and
BMP-6 [60]. However, in terms of chondrogenic potential, the data are controversial compared with those for
BM-MSCs. Thus Afizah et al. [69] reported that better results were obtained in vitro using BM-MSCs; histological,
immunohistochemical, and GAG analyses showed that type II collagen and proteoglycans were synthesized by
BM-MSCs but not ADSCs. However, other authors found no significant differences between the two cell types
[70]. Recent clinical studies have highlighted the use of ADSCs, and phase I and II trials have shown that intraarticular
injection of ADSCs yielded glossy white cartilage similar to native cartilage, although the optimal number of injected
cells remains unclear [71].

18.4.1.2.3 UMBILICAL CORD
The umbilical cord is an important source of stem cells affording promising results in terms of cartilage tissue engi-
neering. In recent years, several researchers have used this new source of stem cells for cartilage regeneration. Umbil-
ical cord blood–derived mesenchymal stem cells (CB-MSCs) are principally used to this end, both in vitro and in vivo
[62]. In terms of culture conditions, the effects of hypoxia or normoxia on hypertrophy of chondrocytes derived from
CB-MSCs are controversial. Gómez-Leduc et al. [72] determined that initial normoxia followed by a period of hypoxia
aided expression of chondrocyte-specific markers, as did the addition of TGF-β1 and BMP-2. Initial normoxia favored
chondral differentiation and hypoxia helped to stabilize the chondrocyte phenotype. Other studies also emphasized
the utility of hypoxia, which improved the expression of chondrocytic markers such as Sox-9 and type II collagen [73].
However, Desanc e et al. [74] found no differences in hypertrophic chondrocyte marker (collagen X and MMP-13) levels
on normoxic or hypoxic culture.
In vivo studies using CB-MSCs combined with HA hydrogels have been performed both in animal models and
clinically in osteoarthritic patients. GAG-rich cartilage developed in the defects; the amount was greater than when
BM-MSCs were used, and collagens of type X and II were also present [75]. Also, arthroscopy revealed firm hyaline
cartilage [76].
Another interesting study using a rabbit osteochondral defect model employed human umbilical cord Wharton’s
jelly–derived mesenchymal stem cells (hWJ-MSCs), which are less immunogenic than other adults MSCs. Hyaline-like,
completely integrated neocartilage was obtained using undifferentiated hWJ-MSCs; the cartilage was of better quality
than that obtained using TGF-β-induced, differentiated hWJ-MSCs [77].

18.4.1.2.4 DENTAL PULP
Human dental pulp stem cells (hDPSCs) are self-renewing MSCs located within the perivascular niche of the pulp
[78]. DPSCs are easily obtained and, under specific conditions, can differentiate in vitro into a variety of cell types,
including chondrocytes [79, 80]. Some studies showed that DPSCs cultured in chondrogenic medium expressed type
I and II collagen [81] along with other chondrogenic markers such as aggrecan, Sox9, and alkaline phosphatase [82].In
a recent study, significant upregulation of chondrogenic genes was evident upon culture in 3-D hydrogel scaffolds
composed of a composite of methacrylated gelatin–HA; thus, a 3-D environment was required for chondrogenic dif-
ferentiation of not only DPSCs but also other chondrogenic cells.
We recently found that after 6weeks of culture under chondrogenic medium, hDPSCs expressed both aggrecan and
low levels of type I and II collagen. In fact, we sought to repair osteochondral defects in rabbits using either hDPSCs or
primary rabbit chondrocytes embedded in 3% (w/v) alginate. After 12weeks, we observed improved tissue regener-
ation and a smoother articular surface when hDPSCs rather than primary chondrocytes were used, which may reflect
the antiinflammatory effects of hDPSCs [54].

18.4.1.2.5 PERIPHERAL BLOOD
Peripheral blood (PB) is an easily accessible source of MSCs useful in cartilage regeneration. Granulocyte-colony
stimulating factor efficiently enriches hematopoietic stem/progenitor cells in peripheral blood [83].
Several studies have compared the chondrogenic potential of PB-MSCs with that of BM-MSCs. In terms of morphol-
ogy and GAG production in vitro, both types of cells exhibited similar behavior, but PB-derived cells exhibited a
greater chondrogenic differentiation potential than BM-MSCs [84]. Using an in vivo defect model in rabbits, similar
findings were noted.
Clinical studies in patients have confirmed the effectiveness of PB-MSCs injected in combination with HA [85, 86].
Histological evaluation of regenerated cartilage and magnetic resonance imaging data showed that the results were
better than those afforded by HA alone.

II. MECHANOBIOLOGY AND TISSUE REGENERATION