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Unformatted text preview: ed in enhanced perfusion in the ischemic limb compared to the
implantation of blank scaffolds (B).
PNAS ∣ October 19, 2010 ∣ vol. 107 ∣ no. 42 ∣ 17937 terns, and avian feather size and spacing (35–37). The polymer
system described in the present paper is also robust against fluctuations in angiogenic VEGF threshold and initial encapsulated
mass. Similarly, natural processes employ mechanisms to enhance the robustness of morphogen gradients against fluctuations
in gene dosage or environmental conditions (38). These mechanisms include self-enhanced degradation (39), complexes with
restricted diffusion (40), feedback (41), or their combination.
In the polymeric system described, since VEGF and anti-VEGF
have a canceling effect, increased doses in both of these proteins
will likely not affect the width of the APR. In order to alter the
width of the APR, VEGF and anti-VEGF doses are expected to
be inversely adjusted.
Many researchers have proposed the delivery of multiple
agents with different release methodologies in order to address
complex biological events (1, 42, 43). This study achieves spatial
restriction and temporal stability of an active concentration profile of a drug by simultaneously delivering a direct inhibitor. containing layers were comparable to previous studies with
protracted release of VEGF (18, 20). Despite the reduction in
total active VEGF delivered in the AVA scaffolds, the resulting
vessel densities and perfusion in the scaffold and in the underlying muscles were not statistically different from those of the
scaffolds delivering VEGF only. The AVA scaffolds also showed
moderate improvement in preventing necrosis compared to
VEGF only and BVB. The free-VEGF concentration in the V
and BVB scaffolds likely was an oversaturating dose, or the excessive VEGF created nonproductive vasculature in these conditions (9, 10, 34). Another possibility is that the lowered
microenvironmental VEGF concentration in the AVA condition
resulted in more structurally effective blood vessels in the central
layer that compensated for the reduced blood vessel densities in
the two side layers.
Aside from a reduction in the concentration of the free activator, VEGF, the initial spatial separation of the inhibitor and
activator lead to a spatially sharp and restricted angiogenic
region. This methodology mimics developmental processes in
nature that use opposing factors as a method of control. Reaction-diffusion mechanisms involving an inhibitor and an activator
manifest in murine interfollicular patterns, angelfish skin pat- ACKNOWLEDGMENTS. Financial support was provided by Wyss Institute and
by National Institutes of Health R01 HL069957. We also thank Biological
Resources of the National Cancer Institute for providing VEGF for our studies. 1. Richardson TP, et al. (2001) Polymeric system for dual growth factor delivery. Nat
2. Bonauer A, et al. (2009) MicroRNA-92a controls angiogenesis and functional recovery
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