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the stiffness of the material and the type of stem cell under investigation. A study by
Chowdhury et al. ( 2010 ) demonstrated that mESC cultured on soft substrates fabri-
cated from polyacrylamide (PA) gels (0.6 kPa) maintained their pluripotent state in
contrast to when they were cultured on rigid substrates such as polystyrene
(>4 MPa). On the other hand, Cozzolino et al. ( 2016 ) reported that resident liver
stem cells (RLSCs) differentiated within 24 h after being cultured on PA gels with
an elastic modulus matching the stiffness of healthy liver (0.4 kPa). In contrast,
when cultured on PA gels with a stiffness of 80 kPa (corresponding to the stiffness
of fibro cirrhotic parenchyma), RLSCs maintained their phenotype, delaying the
onset of hepatocyte differentiation process. In the natural biological environment,
the behaviour of cells is dictated by the structure and mechanical properties of the
tissue. As such, one main design criteria of biomaterial-based approaches is tune-
able mechanical properties, which led to intense research interests in polymers. The
diversity of existing synthetic and natural polymers, coupled with the ability to
design new types of polymers can readily produce biomaterials with controlled
properties. Hydrogels, which are crosslinked 3D polymeric networks, are predomi-
nantly used when the stiffness of the substrate needs to be adjusted; this is mainly
because the mechanical properties of the hydrogel can be tuned by adjusting the
crosslinking density (Mawad et al. 2007 , 2012 ). Hydrogels could be fabricated cov-
ering a large range of mechanical properties (very soft, ~ < 1 kPa to very stiff, ~
500 kPa). They can also be fabricated from natural polymers such as alginate, chi-
tosan, gelatin or synthetic polymers such as polyacrylamide (PA), poly(vinyl alco-
hol) (PVA) and poly(ethylene glycol) (PEG). The reader is referred to a
comprehensive review by Tsou et al. ( 2016 ) describing how different type of hydro-
gels interact with different type of stem cells.
13.2.2.3 Summary
Surface topography, stiffness and type of polymer all play a crucial role in determin-
ing the fate of stem cells. Although the actual mechanisms are still not well defined,
protein adsorption on the poymeric surface is a key factor. The conformation, orien-
tation and quantity of adsorbed protein allow cell attachment via integrin receptor
(Dee et al. 2003 ; Dalby et al. 2014 ). Furthermore, cell surface integrins play an
important role in the interaction of stem cells with the surrounding matrix and are
described as vital for their self-renewal (Lee et al. 2010 ; Kohen et al. 2009 ). As such
the physicochemical properties of polymers play a significant role in modulating
cell-matrix interactions. For example, anionic polymers such as poly[(methyl vinyl
ether)-alt-(maleic acid)] (PMVE-alt-MA) that bears carboxylic and sulfonic groups
can bind to growth factors enabling cell attachment (Brafman et al. 2010 ). hPSCs
cultured on PMVE-alt-MA exhibited higher expression levels of integrins.
Consequently, these polymers are demonstrated to support ex vivo expansion of
hPSCs while maintaining their undifferentiated state.
D. Mawad et al.