Biomedical Engineering Reference
In-Depth Information
differentiation, and survival, and ultimately lead to spatially and temporally
guided tissue and organ development. Growth factors usually act as local me-
diators at very low concentrations (about 10
-9
-10
-11
M), and control over
their signaling activity is mediated through the existence of a biological deliv-
ery system. This dynamic system tightly connects growth factor availability,
and, thus, signaling activity, to specific cellular needs and involves both intra-
cellular and extracellular control mechanisms [1, 2].
A major aim of medicine is now to generate or regenerate functional tis-
sues to replace lost or compromised tissues and organs, and the rapidly
evolving field of tissue engineering increasingly seeks to exploit growth factor
signaling pathways to accomplish these goals. The three common strategies
presently pursued in tissue regeneration and engineering include (A) con-
duction (i.e., implantation of biomaterials that provide structural support for
ingrowth of the desired healthy host cells), (B) induction (i.e., delivery of
growth factors promoting tissue regeneration), and (C) the transplantation of
cells capable of participating in tissue regeneration [3, 4]. Growth factors act
as potent tissue-inducing substances and may either be administered alone,
or in combination with the conductive and cell transplantation approaches.
The goal in growth factor delivery strategies for tissue regeneration is
to mimic physiological signaling and achieve biologic functionality. Growth
factors restore tissue functions by locally signaling to specific target cell pop-
ulations. At the same time, signal propagation to more distant, nontarget cells
is minimized and this allows for reduction of undesired side effects. Eluci-
dation of cellular proliferation and differentiation cascades furthermore has
revealed that isolated signaling of a single growth factor is oftentimes not
sufficient for regeneration of functional, mature tissues; but rather simultan-
eous or sequential cooperation of multiple growth factors may be required
for therapeutic efficacy. Temporal and spatial control over the bioavailability
of growth factors is critical to all of the above processes. With the aim of re-
constituting tissue functions, biomimetic delivery systems may be required
to recapitulate these physiological patterns (i.e., to provide growth factors in
a controlled localized and sustained fashion).
Because of the central importance of new blood vessel formation in almost
all regenerative processes, the design of strategies for delivery of factors that
promote the formation of new blood vessels (angiogenesis) is of particular
interest. Blood vessels not only provide nutrients and oxygen to cells and re-
move waste products, but also supply soluble factors and circulating progenitor
cells critical to tissue repair. First discovered and termed “vascular permeabil-
ity factor” (VPF) by Dvorak and co-workers in 1983, and cloned in 1989 by
Ferrara and co-workers, VEGF has been intensively examined for its role in
blood vessel formation [5, 6]. The central importance of VEGF in development
is highlighted by the finding that a 50% reduction in its expression results in
embryonic lethality [7, 8]. Since its cloning, recombinant VEGF is available in
large quantities, making it an attractive molecule for therapeutic applications.
