ARUP; ISBN: 978-0-9562121-5-3 - CMBBE 2012 - Cardiff University

CHARACTERIZING THE MECHANICAL MICROENVIRONMENT OF 3D
CELL CULTURES USING INDIVIDUAL-BASED MODELS
B. Smeets 1 , T. Odenthal 1 , H. Van Oosterwyck 2 , and H. Ramon 1
1 ABSTRACT
1 KU Leuven - MeBioS, Kasteelpark Arenberg 30, 3001 Heverlee
2 KU Leuven - Biomechanics Section, Celestijnenlaan 300c, 3001 Heverlee
The influence of the mechanical microenvironment on proliferation of progenitor cells in 3D suspension
cultures is still poorly understood. We developed a software framework for individualbased
modeling of three-dimensional cell cultures. The model simulates the proliferation of progenitor
cells on microcarriers. The mechanics of the cells are modeled by the Johnson-Kendall-
Roberts potential and the equations of motion of the cells are derived for a friction-dominated
system. The cell cycle is broken up into two stages: increase of cell volume and cytokinesis. The
microcarriers were simulated with different coating properties and the predicted mechanical stress
levels were compared. The simulations show that both compressive and tensile stresses are present
and that the stress distribution is strongly influenced by the microcarrier coating properties. These
results give an indication that in the future, individual cell-based modeling methods may become
a more widely used tool in combination with in vitro experiments in order to optimize cell culture
processes.
2 INTRODUCTION
Three-dimensional cell cultures are essential for achieving consistent in vitro proliferation, differentiation
and migration. How cells will grow and differentiate is influenced for a large part by
soluble cues, such as growth factors and cytokines, but also by the mechanical environment [1, 6].
Evidence demonstrates that cell-generated forces can promote cell differentiation in the absence
of, or even in spite of signals from soluble factors [2, 7]. Therefore, in order to improve process
design for threedimensional cell cultures and to keep a better control over in vitro cell fate, it is
essential to characterize the microenvironment. However, quantifying the mechanical microenvironment
in experiments is challenging: it is hard to measure it directly in living cell cultures, as
currently no measurement technique is capable of doing this without significantly changing the
mechanical environment [3].
Mathematical models can provide information which is hard or impossible to retrieve from in
vitro measurements and facilitate the quick exploration of a vast parameter space while carrying
out fewer expensive and time-consuming experiments. In addition, by reducing the biological
complexity and by offering highly controllable settings, they lead to an improved structured insight
into the underlying biological processes. Hence, in silico models also help generating new
hypotheses on the mechanisms that could determine cell fate in aggregates. Individual-cell based
models provide explicit information about the intercellular interactions that affect each cell. As
the base unit of the model is the single cell, the effect of the microenvironment at the cellular scale
can be captured in a natural way.