Biomedical Engineering Reference
In-Depth Information
1.2 The Challenges of
Mesenchymal Tissue
Engineering
pies. Stem cells can undergo more than
50
rounds of replication and thus provide an
abundant source of cells to repair or regenerate
large regions of tissue. Because stem cells can
differentiate into many different cell pheno-
types, they can be used in situations where
multiple tissues must be generated to restore
organ function. In addition to providing a
source of mature phenotypes, culture-expanded
adult stem cells secrete paracrine factors that
support vascularization of new tissue. Further-
more, in instances where the cells themselves
do not differentiate or produce a requisite
factor for endogenous tissue healing or ex vivo
regeneration, stem cells can be used to deliver
gene therapy that in turn may enhance regen-
eration of the endogenous host tissue [
Unique challenges face those attempting to
reconstruct or repair damaged bone, cartilage,
ligament, or tendon. As the major support and
connective tissues in the body, they must sustain
high mechanical stress. All four tissues are
largely devoid of cells and are made up mainly
of extracellular matrix (ECM) proteins and
minerals. Cartilage, tendon and ligament cells
must all be able to survive in hypoxic condi-
tions, because these tissues are largely avascu-
lar. As a result of this acellularity, these tissues,
when damaged, often heal slowly, if at all. More-
over, the body's healing response diminishes
with age [
12
,
31
,
92
]. These characteristics provide the mes-
enchymal tissue engineer with an abundant,
renewable, and fl exible source of cells that are
capable of generating adequate amounts of
ECM and of providing the enzymes, cytokines,
and growth factors for the remodeling pro-
cesses that are needed for the integration of
implanted tissue.
,
123
].
The tissues that orthopedic surgeons employ
to repair damaged mesenchyme therefore have
great demands on them. Success in using autol-
ogous or allogenic graft materials for mesen-
chymal tissue repair has been mixed, depending
on the size and site of the wound or defect and
the age and health of the patient. Autologous
grafts for bone repair (the “gold standard” in
orthopedics) have been more successful than
autografts for cartilage, tendon, and ligament
[
24
,
28
,
55
,
73
,
79
,
84
,
86
,
100
1.3 Stem-Cell Repair of Bone
15
,
119
]. For example, Brittberg and colleagues
Recently stem cells of both embryonic and
adult origins have been utilized. However, most
early constructs utilized either endogenous or
culture-expanded bone marrow-derived mes-
enchymal stem cells (BM-MSCs). In fact,
orthopedic surgeons have, for many years,
unknowingly utilized endogenous stem cells
for bone repair. Early autograft transplant
studies revealed the healing potential of bone
marrow, soon recognized to contain a thera-
peutically valuable mesenchymal cell popula-
tion capable of generating osteoblasts [
[
% of patients
in a clinical study of femoral condyle cartilage
defect repair that used autologous chondro-
cyte-seeded grafts. On the other hand, the
results for patellar transplants were less impres-
sive, with only one third of the patients having
a successful outcome [
15
] reported positive results for
88
].
Aside from the diffi culties associated with
harvesting autograft material due to donor-site
morbidity and the diffi culty of obtaining
enough donor tissue, a major defi cit of auto-
grafts has been their frequent failure to become
integrated with the surrounding host tissue.
Often the resultant chimeric tissue fails to
attain the properties of the original tissue, so
that secondary grafting procedures are needed.
Loading the graft material with mature pheno-
type cells has increased the amount of graft
integration; however, limitations in the number
of available autologous donor cells restrict the
size of the graft that may be used [
15
].
However, the identifi cation and characteriza-
tion of “stem” cells within this population has
been accomplished only in the last
30
,
88
20
years
[
].
When grown in vitro, these putative stem
cells were found to reside principally within the
adherent cell subpopulation. Researchers have
taken advantage of this adhesive property to
isolate and enrich the cells [
35
,
90
,
93
16
,
17
,
30
,
88
,
].
Stem cells constitute an exciting alternative
to the limitations of the current repair thera-
106
90
]. This remains the principal way in
which MSCs are enriched for use in tissue-
engineering applications.
,
93
