Biomedical Engineering Reference
In-Depth Information
4 Linking Intracellular, Cellular, and Tissue Level Models
4.1 An Integrative Approach
Single-scale models of the types described above all have their own unique
advantages but also limitations. In vivo changes in vascular wall structure depend
critically on interactions at all scale levels, from intracellular signaling to whole
vessel biomechanics. A more complete understanding of the responses of blood
vessels to changes in hemodynamics requires detail at the cellular level that
CMMs alone cannot provide, while many of the functions of SMCs (such as
proliferation and collagen production) result from the integration of so many
signals that experiments to develop rules for a single-scale, cellular level ABM,
are not feasible. Such an integration of signals could be carried out by an ISM,
however. A multiscale, multi-model approach is thus in order, which promises to
build on the strengths of each type of model while compensating for limitations by
offloading them to another model better suited for those specific types of tasks.
Coupling models at different spatial and temporal scales brings forth a whole
new set of challenges, however. In the next two sections, we focus on challenges
unique to each coupling (intracellular to cellular-level, and cellular-level to tissue-
level). We suggest ideas to consider when attempting this approach, and provide
examples from the literature where these techniques have been successful.
4.2 Coupling Intracellular Signaling Models with Agent
Based Models
Rather than building ABMs whose rules treat the cell as a black box, which
provides specific outputs and behaviors given certain combinations of inputs, it is
possible (experimental data permitting) to couple an ABM with an ISM. In this
case, each agent monitors concentrations of extracellular signaling molecules and
runs its own ISM to decide on a particular behavior, including amounts of proteins
to produce. Such a coupling could thereby enable more fine-grained simulations
that more closely replicate in vivo intracellular processes.
One of the areas where cellular-level ABMs can break down is in the combi-
nation of multiple influences on a single output. For example, both TGF-b and
PDGF-AB influence collagen production by SMCs [
58
]. Each biomolecule's
influences can be tested experimentally by varying concentrations applied in
culture, but mapping out responses by SMCs to combinations of growth factors
increases the complexity of the experiment exponentially. Indeed, addition of a
third or fourth growth factor could make the experiment intractable. Hence, these
kinds of experiments are rarely performed in vitro even though they are exactly the
kind needed to inform a cell-level ABM that treats the cell as a black box. For
example, development of a rule for the combined influences of growth factors on
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