Biomedical Engineering Reference
In-Depth Information
property in designing synthetic ECM, a design variable to tune how much the cell is
constrained by micro-/nanotopography should be taken into account. Tuning stiff-
ness (elastic modulus) of the micro-/nanostructure leads to control the effectiveness
of the micro-/nanotopography as a structural constraint.
11.3.2.1
In Vivo
Effectiveness of Mechanical Cues
Mechanical stimuli have long been recognized as a signifi cant factor in regulating
tissue formation, maturation, and functionality (Chen
2008
). Mechanical loading
induces hypertrophy and strengthening of skeletal muscles, tendons, ligaments, and
bones. In addition, mechanical loading improves functionality of stem cell-derived
tissues, for instance, a bioartifi cial cardiac tissue
in vitro
(Thavandiran et al.
2013
;
Kensah et al.
2013
) and tendon
in vivo
(Yin et al.
2010
).
11.3.2.2
Elastic Modulus: A Parameter for Tuning Effectiveness
of Micro-/Nanotopography as a Structural Constraint
A wide variety of cell types, such as human MSCs (Trappmann et al.
2012
; Kuboki
et al.
2012
; Engler et al.
2006
), mouse ES cells (Evans et al.
2009
), fi broblasts
(Wang et al.
2000
; Yip et al.
2013
; Kawano and Kidoaki
2011
), and glioma cells
(Ulrich et al.
2009
), have been reported to respond to the ECM stiffness within the
range of
in vivo
tissue elastic modulus from 0.1 kPa in the brain to 100 kPa in pre-
calcifi ed bone (Discher et al.
2009
) (Fig.
11.7a
). This response of cells can be used
to specify strength of the cytoplasm-ECM link (Fig.
11.2
), namely, the effectiveness
of the micro-/nanotopography as a structural constraint.
Specifi cally, on a substrate with low elastic modulus, cell-ECM adhesion spots—
that are linked to an actively contracting actin cytoskeleton—move with the sub-
strate deformation, and the compliant substrate reduces the forces at the adhesion
spots to sustain the substrate deformation (Yip et al.
2013
) (Fig.
11.7b
). The
decreased forces reduce the integrin clustering for normal maturation of focal adhe-
sions, then the actin cytoskeleton is weakly assembled in the cytoplasm, being con-
centrated predominantly in the cortex under the cell membrane (Engler et al.
2006
;
Ulrich et al.
2009
; Paszek et al.
2005
). From the engineering point of view, within
the range of Young's modulus that is low enough for the cells to sustain constant
substrate deformation, the strength of the cytoplasm-ECM link can be modulated to
increase with increasing elastic modulus.
On the other hand, in cells on a stiff substrate, force is suffi cient to facilitate
(Galbraith et al.
2002
) the recruitment and stable association of focal adhesion
proteins to mature focal adhesions. This process leads to the formation of large
and well-defi ned actin stress fi bers in the cytoplasm (Engler et al.
2004
,
2006
;
Ulrich et al.
2009
; Paszek et al.
2005
). In cells on stiff (Young's modulus >20 kPa)
ECM modifi ed to allow stable immobilization of collagen, traction forces pla-
teaus at a limiting value and the ECM deformation decreases with increasing
substrate rigidity. Based on this fi nding, it is expected that the highest effectiveness
