Biomedical Engineering Reference
In-Depth Information
promising pair of soluble factors is VEGF and PDGF-bb, which have been shown
to stimulate sprouting and maturation when delivered sequentially [
77
,
78
].
The time-dependent delivery of multiple soluble factors can be easily simulated in
vitro using microfluidic devices programmed to deliver known amounts of several
different source reagents. In addition, these microfluidic devices can be used in
controlled delivery studies to optimize the soluble factors themselves. For
example, protein-engineered variants of chemotactic factors, which have been
shown to enhance chemotaxis and wound healing [
79
], could be screened quickly
using multiple devices operated in parallel. The use of microfluidic devices to
independently optimize soluble factor concentration profiles, temporal profiles,
and potency can potentially save time and resources compared to traditional
approaches to drug delivery optimization.
In addition to manipulating angiogenesis in native tissue, the creation of vas-
cular networks within tissue-engineered constructs is another area of great
potential. Without a perfusable network to mediate nutrient exchange, tissue-
engineered constructs cannot support cell viability throughout the entire bulk
structure. This challenge involves the use of a biomaterial scaffold, through which
endothelial cells must penetrate and develop into functional blood vessels.
Microfluidic sprouting morphogenesis assays can be used in the high-throughput
screening of candidate biomaterials exposed to specific soluble concentration
profiles. Although natural materials such as collagen and alginate have some
ability to be tailored, novel synthetics, which are multivariately tunable for cell
adhesion, mechanical strength [
80
], immobilized ligand density [
81
], and
cell-sensitive degradation [
82
], are especially suited to this systematic approach.
For example, crosstalk between cell adhesion and growth factor signaling is known
to impact cellular proliferation and migration [
83
] and is likely to affect sprouting
morphogenesis. Engineered matrices can also provide additional anisotropic
signals such as lithographic nanopatterns [
84
], nanofibrous structures [
85
], and
gradients of bound growth factors [
86
], adhesion ligands [
87
], or stiffness [
88
]. All
of these anisotropic microenvironments are expected to interact with and modify
directional signaling from soluble gradients.
Another potential application for these devices is the study of pathological
angiogenesis such as chronic ischemia and cancer angiogenesis. By mimicking
specific characteristics of the diseased tissue within the quantitatively controlled
environment of the microfluidic device, these studies may help to provide sys-
tematic understanding of disease processes by teasing apart interdependent vari-
ables. Ischemia in peripheral arterial disease results from a failure of angiogenesis,
leading to loss of mobility and independence [
89
]. Angiogenesis in cancer, i.e.,
tumor-elicited vascularization, is a critical mechanism of malignancy [
90
].
Mechanistic insight into these complex processes may be gleaned through
reductive analysis of individual components. For example, the microfluidic device
could be utilized to quantitatively examine the effects of paracrine factors secreted
under hypoxic conditions, phenotypic changes displayed by vascular endothelial
cells, or aberrant matrix remodeling, all of which are known to change over the
course of disease progression. The device microenvironment could also serve as an
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