Microenvironment Design for Stem Cell Fate Determination - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 235

3.1 First Generation Materials as Artificial ECM
The first generation materials used as artificial ECM consisted of previously
known materials, used for applications such as drug or cell delivery systems. The
natural materials extensively in use include ECM components and derivatives,
such as collagen [ 20 , 52 , 53 ], fibrin [ 54 , 55 ], gelatin [ 56 - 59 ], Matrigel [ 53 , 60 ],
hyaluronic acid (HA) [ 34 , 61 - 63 ] and materials derived from plants and seaweeds,
such as agarose [ 21 , 64 ] and alginate [ 33 , 51 , 64 - 89 ]. Since collagen is a major
component in native ECM and cells interact with collagen through integrin
binding-mediated interactions, 3D collagen gels have been widely used for stem
cell encapsulation, including MSCs [ 20 ] and ESCs [ 52 , 53 ]. Gelatin is a product of
collagen denaturation and as a porous scaffold it has been used for stem-cell-based
tissue engineering applications due to its biocompatibility and lack of antigenicity
[ 56 - 59 ]. Matrigel, a basement membrane matrix, extracted from Engelbreth-
Holm-Swarm (EHS) mouse sarcoma cells, is rich in ECM-derived molecules and
has been investigated extensively for the culture of stem cells. The complexity and
derivation from natural tissues has motivated its use in cultures, particularly for
ESCs, due to its mimicking of natural structures [ 53 , 60 ].
Polysaccharides have been also used to form matrices. Hyaluronic acid (HA) is
a polysaccharide found in many tissues and has been modified to form photo-
polymerized hydrogels with controlled properties that allow for the encapsulation
of viable cells. Cells may interact with HA through receptor binding, primarily
CD44, and HA is degraded by hyaluronidases. Therefore, HA-based biomaterials
have been utilized to regulate stem cell chondrogenic and osteogenic differentia-
tion [ 62 , 63 ]. Since it is one constituent of the ECM present during the early stages
of embryogenesis, HA was used for the development of microenvironments that
inhibited hESC differentiation [ 34 ].
Alginate is a seaweed-derived polysaccharide that forms hydrogels through
ionic cross-linking. Although there are no direct cellular interactions, alginate
forms stable hydrogels that become soluble through the dissociation of the
crosslinks in the network due to the exchange of calcium by sodium ions. These
hydrogels have been extensively used the encapsulation of stem cells for a variety
of applications both in vitro and in vivo [ 67 , 90 , 91 ]. Moreover, alginate has also
been used in the form of macro-porous scaffolds for the cultivation and differen-
tiation of both ESCs [ 33 ] and MSCs [ 81 ].
Natural materials present some challenges. Since they usually are not well-
defined and have a lot-to-lot variability, control over matrix mechanical properties
and degradation rates is limited [ 92 ]. Moreover, naturally derived materials may
provoke immune responses or harbor microbes or viruses [ 93 ]. Furthermore, such
materials are often difficult to process without disrupting a potentially important
hierarchical structure. In addition, hydrogels formed from natural materials gen-
erally have poor mechanical properties.
Synthetic materials are being widely investigated for stem cell culture. The
wide diversity of matrix properties is tailored with respect to mechanics, chemistry