Microenvironment Design for Stem Cell Fate Determination - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 252

Although rotary vessels have improved mass transfer to the construct surface,
they did not solve the problem of the limiting internal mass transfer within the
construct. To address this challenge, perfusion bioreactors, designed to force the
culture medium into the cell constructs, have been developed [ 69 , 88 ] and shown
to be superior to conventional bioreactors. For example, 3D cultivation in perfu-
sion bioreactors was shown to encourage MSC expansion and their subsequent
osteogenic differentiation in vivo [ 198 ]. Sikavitsas et al. [ 199 ] have shown that
fluid flow not only mitigates nutrient transport limitations in 3D perfusion cultures
of MSCs, but also provides mechanical stimulation to seeded cells in the form of
fluid shear stress, resulting in increased deposition of mineralized matrix. Cellular
constructs cultured in a flow perfusion bioreactor yielded a significant increase in
matrix mineralization after 16 days compared with those cultured statically, when
cultured in the presence of osteogenic supplements [ 200 ].
Our group has developed a novel perfusion bioreactor that is capable of cul-
tivating multiple 3D cellular constructs in one flow chamber. Its unique features
provided a homogeneous fluid flow along the bioreactor cross-section and maxi-
mal exposure of the cellular constructs to the perfusing medium. By employing
this advanced perfusion bioreactor, cardiac cell constructs were shown to maintain
almost 100% of the seeded cells viable, while less than 60% of the cells in static
cultures were viable after 7-day cultivation [ 69 ]. Moreover, a thick ([500 lm)
cardiac tissue was generated, composed of elongated and aligned cells with a
massive striation, resembling the native adult heart [ 88 ].
In addition to the great advantage of superior mass transport, bioreactors can
also provide control over the cellular environment in terms of biochemical and
physical regulatory signals, such as mechanical and electrical stimuli, and enable
on-line monitoring and response [ 87 , 201 ]. For additional information on the
potential utilization of advanced bioreactor systems for stem cell expansion and
differentiation, the reader is referred to the reviews in [ 13 , 202 ].
5 Conclusions and Future Directions
Biomaterials with controllable physical, chemical and biological properties are
potentially a powerful tool for directing stem cells towards expansion or specific-
lineage differentiation. Clearly, the studies presented point out the tremendous
potential in using bio-inspired biomaterials for stem cell applications. However,
this field is still in its earliest stages. We still need to better understand the full,
complex and dynamic interplay between the key parameters of the microenvi-
ronment controlling stem cell fate. This knowledge will enable the creation of
novel intelligent biomaterials that combine the advantages of native and synthetic
materials. These biomaterials should be sophisticated enough to elicit in vivo like
cell responses yet simple and practical enough for use in biology and medicine.
These advanced materials may incorporate the spatial presentation of multiple
regulatory molecules (such as peptides and growth factors), with temporally