Biomedical Engineering Reference
In-Depth Information
combinations of extracellular signals are most
effective in inducing bone formation. Species
differences in the response of osteoblast pro-
genitor cells to osteogenic stimuli are known
[
(PlGF), hepatocyte growth factor, and trans-
forming growth factor
].
Moreover, as in wound sites, these cytokines
increase in quantity when the cells are exposed
to hypoxic conditions [
β
(TGF-
β
) [
54
,
57
,
96
], but they need detailed characteriza-
tion. Rat BM-MSCs readily adhere to and pro-
liferate on an alginate gel surface, whereas
human cells fail to adhere, unless type I colla-
gen or
21
,
65
,
69
]. When adult
stem cells are placed into models of hind limb
ischemia, collateral perfusion is increased [
57
,
58
,
96
].
Stem cells therefore not only can differentiate
into osteoblasts, but may also support vascu-
larization of the new bone. Understanding how
this response is regulated is critical not only to
engineering bone, but also to the successful
utilization of stem cells in generating avascular
mesenchymal tissues such as cartilage. It must
be remembered that too high a level of oxygen
within cartilage can induce apoptosis [
58
β
-tricalcium phosphate is added to the
gel [
] reported
that BM-MSCs, when predifferentiated prior to
transplantation in a rabbit tibia defect, gave
rise to radiographically signifi cant amounts of
bone, whereas, as mentioned previously, human
MSCs exposed to similar conditions did not
substantially increase bone formation [
64
]. Srouji and colleagues [
63
].
Stem cells are exposed not only to chemical
stimuli and scaffold interactions, but also to
physical forces that act on these cells during
the engineering process and after transplanta-
tion. Limited studies have been performed;
however, application of physical force to the
cells prior to transplantation seems to modu-
late their differentiation into osteoblasts. When
human adult stem cells are exposed to either
constant or intermittent mechanical or sheer
stress, increased levels of osteogenic gene
expression and mineralized matrix formation
are observed [
108
72
].
1.5 Safety and Success
An important challenge for the tissue engineer
is to assess the safety of human stem cells when
they are used to form bone in vivo. Even in
severely immunocompromised rodent models
such as the NOD/SCID mouse, there appears to
be at least a low-level immunological response
to the MSCs, to the scaffolds onto which they
are seeded, or both [
].
Adequate oxygenation is critical to the suc-
cessful generation and grafting of stem-cell-
derived bone. Prior to implantation, cells must
be adequately oxygenated so that they can
expand into multiple layers and migrate into
the inner surfaces of the delivery scaffolds.
Current culture systems cannot yet surpass the
150
49
,
59
,
74
,
77
,
98
]. This response depends
on differences in how the cells are isolated or
expanded in vitro prior to transplantation. It
has been argued that the safety of autologous
stem cells used for tissue engineering of bone
in preclinical studies should be an adequate
indicator of human stem-cell safety. Indeed,
human BM-MSCs not only are immunoprivi-
leged but also can suppress immune function
[
122
m limit of nutrient and oxygen
penetration. For large defects in human long
bones, for example, grafting tissues with thick-
nesses in the millimeter range would signifi -
cantly decrease the time required for bone
repair. To avoid cell necrosis, transplanted
stem cell/scaffold constructs must be integrated
rapidly into the recipient's vascular system.
When grow t h factors such as vascu lar endot he-
lial growth factor (VEGF), which stimulates
vascularization, were made part of scaffolds,
bone formation was found to be signifi cantly
enhanced [
- to
200
-
µ
]. In the end, however, the answer to this
question lies in the results of clinical trials yet
to be undertaken.
Notwithstanding the many as yet unan-
swered questions, the use of human stem cells
for bone repair has yielded encouraging initial
results. Culture-enriched autologous BM-MSCs
have been used to successfully treat refractory
atrophic and hypotrophic nonunion fractures
in a small phase I clinical trial in Spain [
2
].
Another case report from Germany describes
how autologous ADSCs were used in combina-
tion with bone marrow to treat a nine-year-old
girl who had sustained critical cranial defects
as a result of trauma. Signifi cant bone forma-
tion was demonstrated after only
87
].
Both adipose-derived and bone-marrow-
derived stem cells can induce new blood vessel
formation, because they synthesize physiologi-
cally signifi cant amounts of angiogenic cyto-
kines, including VEGF, placental growth factor
44
,
66
,
81
3
months
[
67
]. Previous attempts at using autologous and
