ENGINEERING ARTIFICIAL STEM CELL NICHES - Biologically-Responsive Hybrid Biomaterials - page 288

nascent tissues. Remarkably, vascular cells formed 3D capillary-like structures
that extended across an intervening gel to the hepatocyte tissues. Since
microvascular networks are considered to be important components of stem cell
niches, this approach of 3D engineered tissues in vitro in a microfluidic
environment should have interesting applications to address fundamental
questions in stem cell biology.
2.5. 3D biomolecule gradients as model niches
A question of paramount importance in developmental and stem cell biology is
how protein morphogen gradients regulate cell fate and tissue or organ
development. Biomolecule gradients are indeed crucial regulatory components of
dynamic tissue processes, not only during development, but also homeostasis and
regeneration. Therefore, biomolecule gradients should become an important
element of the emerging 3D biomaterials toolbox for stem cell biology. Protein
gradients can be exploited in two ways: First, as a means of high-throughput
screening for the optimal dose of stem cell signaling molecules. In this case, a
large number of individual stem cells can be exposed to a relatively large-scale
gradient, each cell being exposed to different protein concentration. Second,
steeper gradients can serve as a means to probe the effect of a gradient on the fate
of one single stem cell. Thereby, the individual cell could sense two different
biomolecule concentrations across its length, possibly influencing directional
stem cell migration in chemotaxis, such as in stem cell homing, or the symmetry
of stem cell division (symmetric vs. asymmetric division). Arguably the most
precise and robust way of generating biomolecule gradient is using microfluidic
technology. 84 Microfluidic gradient platforms have already been applied to stem
cell biology, albeit in 2D, (e.g. 85 ). However, 3D gradient systems are rapidly
emerging. 86,87 Choi and colleagues have for example presented a microfluidics-
based approach whereby cells within alginate gels could be exposed to desirable
soluble gradients in 3D microenvironments. 86 Applied to adult stem cell culture,
such intricate control over the biochemical microenvironment in 3D constitutes
an important step towards the in vitro recapitulation of more complex stem cell
microenvironments. The advantages of combining biomaterials engineering with
microfluidics for such applications are clearly apparent, since apart from
affording excellent spatiotemporal control in biomolecule presentation,
microfluidic technology also allows to array cell culture chambers that are
individually addressable. 88 Since many protein morphogens are bound to the