Biomedical Engineering Reference
In-Depth Information
showed that NSCs cultured on variable modulus substrates differentiate pref-
erentially into neurons on softer substrates and astrocytes on stiffer materials
[
128
]. In addition to differentiation, matrix elasticity can influence stem cell self-
renewal. For instance, it was observed that 2-D soft substrates promote the ability
of embryonic stem cells [
129
] and adult muscle stem cells [
130
] to self-renew in
culture.
However, it is important to note that most studies of stem cell mechanotrans-
duction have been performed with 2-D substrate systems [
128
-
130
], which lacked
the 3-D complexity of the naive tissue environment. How stem cells sense and
respond to the mechanics of their 2-D or 3-D microenvironments can be very
different, resulting in changes in cell functions. This disparity in cell functions
have been shown in studies, where cells showed increased spreading and motil-
ity on stiff 2-D matrix, but were confined to the 3-D matrix that it must degrade
or deform [
131
]. One of the major challenges in understanding mechanosensitiv-
ity within 3-D microenvironments is the ability to decouple the effects of matrix
mechanics from that caused by crosslinking density and porosity, since increased
mechanics is often caused by increased crosslinking density that results in
decreased mesh size and permeability.
While the matrix composition and mechanical structure determine the stem cell
proliferation and differentiation, the matrix degradation rate influences the cell
migration, matrix deposition, remodelling and tissue morphogenesis [
131
]. A vari-
ety of different systems have emerged to better control gel degradation. Hydrogels
can be designed to undergo hydrolytic or enzymatic degradation where the latter
allows for biomimetic control over local degradation dictated by the amount of
cell enzyme secretion and the susceptibility of the cross-linker peptide sequence.
The importance of cell-mediated gel degradation has been shown in studies to pro-
mote stem cell growth and differentiation as well as in neotissue formation where
rate of gel degradation should match the rate of cell growth and matrix deposition
in neotissue formation. Light may also be used to control hydrogel degradation,
where photodegradable networks can be created that can undergo reverse gela-
tion under cytocompatible conditions. These photodegradable hydrogels allow the
greatest advantage of external control of degradation and in situ tuning of hydro-
gel mechanics. Seliktar and colleagues have used high-intensity pulsed laser light
to photoablate guidance channels in transparent hydrogels to guide neural growth
into the gel, which opens potential for treating nerve injuries [
132
].
4.2 Growth Factors and Biomolecules
Morphogens have been known to regulate cell fate and tissue morphogenesis dur-
ing development [
126
] and represents the most potent and direct regulation of cell
fate and function towards the lineage-of-interest [
8
,
133
]. Many of these soluble
factors are immobilized to the ECM framework via matrix-binding domains. The
spatial distribution of factors with local and/or gradient concentrations, duration
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