Microenvironment Design for Stem Cell Fate Determination - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 247

induced cardiomyocyte cell cycle re-entry, an indication of endogenous regener-
ation of cardiac muscle [ 83 ].
Alginate-sulfate has several advantages over the use of heparin, as it forms a
stable non-immunogenic hydrogel when combined with unmodified alginate, and
its mass production may be achieved at relatively low cost compared to that of
heparin. In contrast to alginate, exogenous delivered heparin and heparan sulfate
molecules are rapidly degraded in the human body and thus they have limited use
as a prolonged and efficient drug delivery system. Moreover, heparin and heparan
sulfate are very heterogeneous macromolecules with multiple biological functions
beyond being a depot for growth factors, and thus controlling their behavior and
effect in vivo is limited. For example, heparin, commonly used as an anticoagulant
drug, was recently suggested also to play a key role in inflammatory processes
[ 174 ].
Thus, we believe that the affinity-binding platform of alginate-sulfate will be a
powerful tool in the design of stem cell microenvironments that better mimic the
natural presentation and release patterns of the inductive cues which control stem
cell fate decision.
3.2.3 Matrix Chemistry
A different strategy utilizing simple matrix chemistry has recently been introduced
to fine-tune the subtle design of the stem cell microenvironment, or, in other cases,
even to create inductive microenvironments without the use of the conventional
natural regulatory molecules.
A good example of microenvironment fine-tuning is the photo-degradable
hydrogels, developed for ''on-demand'' degradation of the physical network
structure [ 175 ]. These hydrogels are prepared by cross-linking via photo-labile
moieties. Thus, the degradation rate and extent as well as the resulting material
properties, such as stiffness, can be predictably manipulated with light intensity
and wavelength. This precise control of gel cross-linking density was used to
examine the influence of gel structure on hMSC spreading. These cells exhibited
rounded cell morphology within a densely cross-linked gel; however, when the gel
cross-linking density was reduced through photo-degradation, cell spreading was
observed. Thus, cell morphology can be manipulated by irradiation and degra-
dation of these hydrogels at any time in culture. Moreover, photo-degradable
linkages can also be exploited to locally modify the chemical environment within a
hydrogel by incorporation of tethered, but photo-labile, biologically active func-
tionalities. For instance, a photo-labile group was coupled to the adhesive peptide
RGD, and incorporated into PEG-based hydrogel, producing a hydrogel with
photolytic control over its chemical interaction with encapsulated cells. The
temporal presentation of the adhesive RGD peptide was shown to be beneficial for
hMSC chondrogenic differentiation [ 125 ].
A recent study by Benoit and co-workers pointed out the possibility of
controlling stem cell decision by using simple chemistry alone. The researchers