Biomedical Engineering Reference
In-Depth Information
integration with surrounding cartilage and subchondral
bone is important. Otherwise, the osteochondral repair
construct would delaminate or subside. A lack of the
integration is the reason in part why tissue engineering
approaches to osteochondral defect repair have had
limited success. In an attempt to enhance the integration,
tissue engineering strategies have utilized heterogeneous
constructs in which the upper region promotes cartilage
repair while the lower region is specifically designed to
encourage bone integration. The ability of chondrocyte-
seeded scaffolds to promote repair of the subchondral
bone has been variable, due in part to differences in the
chondrocyte phenotype within tissue-engineered carti-
lage constructs. The cellular component of an osteo-
chondral repair strategy may provide critical signals for
enhancing bone repair that are intrinsically lacking in an
acellular or devitalized implant. During growth and en-
dochondral bone repair, chondrocytes progress to a hy-
pertrophic phenotype and play an important role in
angiogenesis, osteoblast recruitment, and mineralized
matrix formation. Conversely, articular chondrocytes do
not express osteoinductive factors and may inhibit bone
formation by producing antiangiogenesis factors such as
tissue inhibitors of metalloproteases and troponin.
Therefore, chondrocytes within a tissue-engineered car-
tilage construct have the potential to influence adjacent
bone repair response.
Chondrocytes
in vivo
respond to chemical stimuli as
well. Two such biochemical regulators of matrix bio-
synthesis found in articular joints are TGF-b1 and IGF-I.
The IGF-I enhances matrix biosynthesis and mitotic
activity in chondrocytes, decreases matrix catabolism,
and can enhance the tissue properties of cartilage ex-
plants in long-term culture. The TGF-b1 exerts a similar
influence on matrix biosynthesis, directing production
toward increased amounts of larger, more anionic pro-
teoglycan species.
The phenotype change is well known for chondrocytes
which are responsible for the hyaline cartilage consisting
of type II collagen in the normal articular cartilage, but
under irregular culture conditions the same cells produce
the fibrous cartilage made from type I collagen which is
inferior to the hyaline cartilage with respect to me-
chanical properties required for articular cartilage. This
means that the cells lose the chondrocyte phenotype and
become fibroblast-like cells.
new functional tissue; they should not be rejected by the
recipient and not turn into cancer; and they must have
the ability to survive in the low-oxygen environment
normally associated with surgical implantation. Mature
adult cells fail to meet many of these criteria. The oxygen
demand of cells increases with their metabolic activity.
After being expanded in the incubator for significant
periods of time, they have a relatively high oxygen re-
quirement and do not perform normally. A hepatocyte,
for example, requires about 50 times more oxygen than
a cell such as a chondrocyte and much attention has
turned to progenitor cells and stem cells. True stem cells
can turn into any type of cell, while progenitor cells are
more or less committed to becoming cell types of a par-
ticular tissue or organ. Somatic adult stem cells may ac-
tually represent progenitor cells in that they may turn
into all the cells of a specific tissue but not into any cell
type. Somatic stem cells can be procured from the in-
dividual needing the new tissue and thus not be rejected.
Since these cells are immature, they will survive a
low-oxygen environment. Somatic stem cells normally
reside within specific extracellular regulatory micro-
environments
consisting of a complex
mixture of soluble and insoluble, short- and long-range
ECM signals, which regulate their behavior. These mul-
tiple, local environmental cues are integrated by cells that
respond by choosing self-renewal or a pathway of dif-
ferentiation. Outside of their niche, adult stem cells lose
their developmental potential quickly.
Somatic stem cells had been claimed to possess an
unexpectedly broad differentiation potential that could
be induced by exposing stem cells to the extracellular
developmental signals of other lineages in mixed-cell
cultures. This stem cell plasticity was thus thought to
form the foundation for one of the multiple prospective
uses of adult stem cells in regenerative medicine. How-
ever, experimental evidence supporting the existence of
stem-cell plasticity has been refuted because stem cells
have been shown to adopt the functional features of
other features by means of cell-fusion-mediated acqui-
sition of lineage-specific determinants (chromosomal
DNA) rather than by signal-mediated differentiation.
Data demonstrating that stem cells could fuse with and
subsequently adopt the phenotypes of other cell types
indicated that the very co-culture assays originally
interpreted to support plasticity instead were artifacts of
cell fusion.
Two types of stem cell are available: ES cells and so-
matic or adult autologous stem cells. The clinical use of
ES cells has critical problems of cell regulation including
malignant potential, allogeneic immune response, and
ethical issues concerning the cell source, while the
problem with autologous stem cells concerns their cell
source. Bone marrow is the most suitable cell source,
because it involves not only hematopoietic stem cells but
d
stem cell niches
d
7.2.8.2 Somatic (adult) stem cells
Mature cells, when allowed to multiply in an incubator,
ultimately lose their effectiveness. Consequently, scien-
tists are turning to other cell types. To be effective, cells
must be easily procured and readily available; they must
multiply well without losing their potential to generate
