Biomedical Engineering Reference
In-Depth Information
intricate coupling mechanisms arising from cell-substrate interaction and intracel-
lular machinery.
3.1 Introduction
Living cells interact with their environments over a wide range of stiffness, from
soft skin through stiffer muscle to harder bone substrates. In such cellular inter-
actions, adhesion of cells to substrates or to an extracellular matrix (ECM) is a
critical feature in many cellular functions, ranging from migration and proliferation
to apoptosis (Boudreau and Bissell,
1998
; Schwartz and Ginsberg,
2002
). Exper-
imental studies have now shown that the mechanical compliance of the ECM or
the substrate influences cell viability, differentiation and motility (Lo et al.,
2000
;
Discher et al.,
2005
; Yeung et al.,
2005
). It is now widely accepted that cells ex-
ert a higher force, form larger focal adhesions and develop thicker stress fibers on
stiffer substrates (Saez et al.,
2005
; Yeung et al.,
2005
). The relationship between
stiffness and intracellular machinery regulates many important functions such as
non-viral gene delivery (Kong et al.,
2005
) and growth of cancer cells (Paszek et
al.,
2005
). Evidence suggests that increased rigidity may trigger malignant transfor-
mation (Paszek et al.,
2005
), attributable to increased cytoskeletal tension, integrin
clustering and focal adhesion formation.
The experimental studies by Saez et al. (
2005
) and Yeung et al. (
2005
) clearly
demonstrate a direct dependence of cell behavior on substrate stiffness. In these
studies, cellular activity, measured in terms of the average force exerted by the cell
on the substrate, the size of focal adhesions, and the concentration of stress fibers,
rose to greater levels on stiffer substrates. In addition, the experimental studies of
Tan et al. (
2003
) and Chen et al. (
2003
) provide further data regarding the shape and
size of cell-substrate adhesions and the scaling of forces relative to the spread area
of the cell.
A recently developed biochemomechanical model by Deshpande et al. (
2006
,
2007
,
2008
) characterizes the dynamically contractile stress fiber machinery made
of actin-myosin filaments, giving rise to intracellular force generation, as well as
focal adhesion assembly, the latter based on thermodynamic equilibrium between
integrins in their low and high affinity states. This model has been successfully
employed in simulations of experiments, including cell adhesion on V, T, Y and U-
shaped patterned substrates (Pathak et al.,
2008
), and the formation of stress fibers
upon cyclic stretching (Wei et al.,
2008
). We utilize a similar approach to simulate
cell behavior on flat gel substrates, and on post-beds of variegated stiffness. While
post-beds offer direct and readily quantifiable insights into the shapes and sizes of
adhesions and the forces applied by a contractile cell, a flat substrate is relevant
due to its presence in living organisms and its use for in vitro studies. Here, we
present simulations for both flat substrates and post-beds, and predict trends in focal
adhesion distribution, tractions and stress fiber distribution common to both types
of substrate architecture.
