255A biomaterial-based approach is being sought to resolve this issue. In contrast to
2D, 3D polymeric constructs have been shown to display many features of the
native myocardium, such as cell-cell interaction, spontaneous beating activity and
increased cardiac specific protein expression (Thavandiran et al. 2013 ). Design cri-
teria of a biomaterial tailored for the heart include: (i) mechanical durability under
continuous strain; (ii) support of contractile functionality of the cardiomyocytes;
(iii) appropriate stiffness; and (iv) conductivity, to help transduce the bioelectric
signal of cardiomyocytes. Elastomeric polymers are being used in cardiac regenera-
tion because of their long-term mechanical stability under exposure to repeated
strain cycles. Examples include poly(glycerol sebacate) (PGS) (Ravichandran et al.
2013 ), poly(urethane) (Alperin et al. 2005 ) and its biodegradable analogue poly(ester
urethane) (Nieponice et al. 2010 ), PLA and PLGA (Chen et al. 2015 ). However,
these polymers degrade into small acidic compounds that can trigger an immune
response in the heart. To accommodate the contractile functionality of the cardio-
myocytes, the stiffness of the scaffold could be modulated. Seeding cardiomyocytes
in 3D PGS scaffolds of varying stiffness (2.35–5.99 kPa), it was found that the
contractile function of the cardiac constructs correlate positively with low stiffness
(Marsano et al. 2010 ). However, this study investigated the role of matrix mechani-
cal properties on the function of differentiated cardiomyocytes. To examine whether
elasticity plays a role in directing cardiac differentiation, tissue culture plates were
coated with polydimethylsiloxane (PDMS), an inert synthetic polymer of tuneable
mechanical properties and embryonic stem cells (ES) seeded on top were monitored
for their development (Arshi et al. 2013 ). The authors reported that the differentia-
tion of pluripotent ES cells into functional cardiomyocytes was better supported by
the rigid PDMS substrate (~1000 kPa) in comparison to their softer counterpart
(~10 kPa).
The interplay between the material stiffness and differentiation into cardiac lin-
eage is not straightforward and requires consideration of not only the material prop-
erties but the polymer chemical composition, the type of stem cells used and the
dimensionality of the construct (2D versus 3D). In a similar work by Battista et al.
( 2005 ) investigating the effect of elasticity of collagen scaffolds on embryonic stem
cells, it was found that cardiac differentiation was significantly inhibited as the col-
lagen scaffold stiffness was increased from 16 to 34 Pa. Also the study investigated
the effect of biochemical cues by introducing laminin and fibronectin in the scaf-
folds. Laminin was found to promote differentiation into beating cardiomyocytes,
whereas fibronectin stimulated endothelial cell differentiation and vascularization.
These studies point out to the complexity of reproducing the extracellular environ-
ment in the laboratory. Not only the polymer chemistry needs to be considered, but
its processing into a scaffold with tuneable mechanical closely matching that of the
tissue is a key factor to achieve the required objective. Also, biochemical cues either
added as soluble factors in the scaffold or anchored covalently on the polymer back-
bone are essential to mediate cell adhesion and direct differentiation of cardiac pro-
genitor cells.
To date, contractile activity of cardiomyocytes has been investigated in: (i) thin
layers (Shim et al. 2012 ; Feinberg et al. 2007 ), (ii) 3D cardiac microtissues generated
13 Current Technologies Based on the Knowledge of the Stem...