Biomedical Engineering Reference
In-Depth Information
composed of fibers that provide geometric and topographic signals to direct cell
functions, cell-cell/matrix interactions, morphogenesis and structural organization
in microscale. To this end, various approaches have been explored in the hydrogel
design and engineering to influence stem cell fate and functions by tailoring the
geometry, topography as well as porosity of the hydrogel.
It is well-known that cell shape and function are tightly-coupled [
115
,
116
].
The change in cell shape is often accompanied not only by changes in the
cytoskeleton assembly but also in cell functions through specific gene and protein
expression. Apart from biochemical control of cell shape by the use of growth fac-
tors or actin-disrupting agents [
117
], biophysical strategies through stiffness con-
trol and micropatterning of hydrogel substrates have also proved efficacious in
guiding stem cell differentiation [
107
,
118
]. Using polyacrylamide hydrogels pat-
terned by photolithography that approximate the mechanical properties of soft tis-
sues, Lee and colleagues have shown that MSCs cultured in small circular islands
show elevated expression of adipogenesis markers while cells that spread in aniso-
tropic geometries tend to express elevated neurogenic markers [
119
].
When the hydrogel mesh size is smaller than the size of cell or protein, the cell
movement and nutrient transport are likely to be affected, but may be overcome by
material strategies including alterations in crosslinking density or tunable degrada-
tion. At a higher level of modification, electrospinning is the technique that has
recently been adopted to fabricate hydrogel nanofibers to mimic the 3D nanofi-
brous structure of the native ECM and to control the biochemical and biomechani-
cal properties [
120
,
121
]. Hydrogel fibrous structure not only allows for improved
cell movement and nutrient transport through increased porosity, but also exerts
topographic control to influence cell fate, and presentation of anisotropic elasticity,
which is important for certain tissues [
122
]. Other strategies to improve the poros-
ity of hydrogels include the use of stimuli-responsive microspheres [
123
], micro-
fibers [
124
] and gel systems [
125
] that may be dissolved in a controlled manner
by specific changes in pH, temperature or exposure to enzymes. One example is
the impregnation of cell-laden gelatin microspheres within the alginate hydrogel,
which upon transfer to 37 °C, allowed the gelatin to be dissolved and released the
cells into the spherical cavities created in the hydrogel bulk, creating space for fur-
ther cell growth within the matrix [
123
]. Lau and colleagues observed enhanced
cell survival and hepatogenesis of murine iPSCs encapsulated in such micro-cavi-
tary hydrogel system [
123
].
4.1.2 Matrix Mechanics and Degradation
In their native tissue environment, cells experience a wide magnitude of matrix
stiffness, from soft (brain ~0.1 kPa) to stiffer (bone ~80 kPa) tissues, which dic-
tates several aspects of cellular functions [
126
]. The landmark study by Engler
and colleagues [
127
] demonstrated that hMSCs cultured on 2-D polyacrylamide
substrates of varying stiffness undergo lineage-specific differentiation to become
cell types characteristic of tissues with the corresponding stiffness. A later study
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