249et al. 2016 ), 3D bioprinting of monolayer cells at high density scaffold- free (“bio-
printed heart on a chip” (Lind et al. 2016 )) or in presence of scaffolds for endothe-
lialization (Zhang et al. 2016 ). Additionally, 3D microfluidic devices can be readily
monitored with several imaging modalities and closely replicate key physiological
and structural features of small functional units of organs. For example, “micro-
channels” can permit physiological flow rates, peristaltic contractions and the
essential function of blood vessels for delivering oxygen and nutrients, while
removing waste (Bhatia and Ingber 2014 ; Huh et al. 2010 ). Miniaturized models of
functional biological units have already been fabricated on a chip, including models
for lung, liver, kidney, intestine, heart, fat, bone marrow, cornea, skin, and the blood-
brain barrier (Bhatia and Ingber 2014 ).
13.2.1.3 Static Versus Dynamic Stem Cell Niche
Although microfluidic-based organ-on-a-chip systems can integrate key compo-
nents together and still allow precise control and measurement in a dynamic envi-
ronment, certain features of static 3D spheroid cultures may still be more
advantageous. For example, spheroids can generate more tissue mass, allowing sci-
entists to perform analytical experiments that usually require large samples. On one
hand, 3D spheroid cultures also allow the growth of macroscale architecture and
highly complex and spatially heterogeneous tissues that cannot be supported at the
microscale. On the other hand, microfluidic chips still offer an unprecedented flex-
ibility in independently controlling and monitoring features such as flow and other
mechanical cues, helping to dissect their contribution to tissue and organ function.
Finally, microfluidics allow fluorescence confocal microscopy analyses of cells,
trans-epithelial electrical resistance measurements, multiple electrode arrays, and
other analytical systems not easily recapitulated in static 3D spheroid cultures
(Bhatia and Ingber 2014 , Huh et al. 2010 ). Therefore, there is growing interest in
integrating 3D spheroid cultures with microfluidics and 3D bioprinting technology
for the engineering of the stem cell niche for both static and dynamic conditions.
13.2.2 Physico-Chemical Approaches to Engineer the Niche
for an Undifferentiated Phenotype
Decades long intensive research has established that synthetic polymers are excel-
lent candidates to serve as platforms for the support of the long-term culture of stem
cells. For instance, Villa-Diaz et al. ( 2010 ) showed the ability of a well-defined syn-
thetic polymer, poly[2-(methacryloyloxy)ethyl dimethyl-(3-sulfopropyl)ammonium
hydroxide] (PMEDSAH), to sustain long-term (~25 passages) hESC growth in sev-
eral different culture media. Short term self-renewal of hESC has been also shown
in a synthetic hydrogel fabricated from poly (N-isopropylacrylamide-co- acrylic
13 Current Technologies Based on the Knowledge of the Stem...