Biomedical Engineering Reference
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Fig. 7 Fibrin matrices. Scanning electron microscopic analysis of fibrin networks. High
molecular weight (HMW) fibrinogen is thicker and forms more open network structures (left
figure) than low molecular weight (LMW) fibrinogen (right figure). Bars represent 1 lm
predictions point out gaps in our understanding. A clear focus point for
improvement is the structure of the extracellular matrix and the interactions of
cells with the matrix.
We could model the extracellular matrix in detail. Endothelial cells strongly
interact with the matrix, mechanically as well as chemically. Cells can adhere to
the fibers in the matrix and rearrange the fibers. By modeling the actual fibers and
their alignment, physical obstruction of the matrix, haptotaxis and directional
guidance of migration can be considered. Endothelial cells can also degrade the
matrix with a sensitive and complicated system of proteolytic enzymes. Proteol-
ysis of the matrix locally releases chemotactic components that stimulate sprout-
ing. Each of these mechanical, haptotactical and chemotactical forces resulting
from the surrounding tissue influence angiogenesis and are therefore important to
understand.
Besides modeling the extracellular matrix more intensively, the interactions
within the cell should be focused on. Endothelial cells adhere to the extracellular
matrix with integrins, which are also linked to the cytoskeleton of the cell.
By modeling cytoskeleton remodeling and integrin-mediated binding at a molec-
ular level, we can study mechanical matrix interaction. Additionally, tip cell
selection is an interesting molecular interaction within and between cells to
include in the model. Tip cell selection depends on Delta-Notch signaling [ 28 ] and
is required for experimentally observed branching of tubes.
In conclusion, we aim to create a multi-level model of angiogenesis that
includes the molecular, cellular and tissue level. Each level should be modeled
simple and intuitively and the interaction between the levels must be taken in close
consideration. To understand which components should be modeled and how they
interact, a continuous feedback between experimental and computational modelers
is needed.
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