Problem#3Mimicking nature by codelivery of stimulant and inhibitor

Problem#3Mimicking nature by codelivery of stimulant and inhibitor

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Mimicking nature by codelivery of stimulant and inhibitor to create temporally stable and spatially restricted angiogenic zones William W. Yuen a , Nan R. Du a , Chun H. Chan b , Eduardo A. Silva a , and David J. Mooney a,1 a School of Engineering and Applied Sciences, Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA; and b Biomedical Engineering, Cornell University, Ithaca, NY Edited by Alexander M. Klibanov, Massachusetts Institute of Technology, Cambridge, MA, and approved August 24, 2010 (received for review February 10, 2010) Nature frequently utilizes opposing factors to create a stable acti- vator gradient to robustly control pattern formation. This study employs a biomimicry approach, by delivery of both angiogenic and antiangiogenic factors from spatially restricted zones of a synthetic polymer to achieve temporally stable and spatially restricted angiogenic zones in vivo. The simultaneous release of the two spatially separated agents leads to a spatially sharp angio- genic region that is sustained over 3 wk. Further, the contradictory action of the two agents leads to a stable level of proangiogenic stimulation in this region, in spite of significant variations in the individual release rates over time. The resulting spatially restrictive and temporally sustained profiles of active signaling allow the creation of a spatially heterogeneous and functional vasculature. controlled drug delivery peripheral ischemia VEGF antibody diffusion reaction Turing pattern S trategies leading to the creation of organized and functional networks of blood vessels are likely to have significant utility in the treatment of ischemic diseases and the engineering of high-dimensional tissues (1, 2). Numerous molecular players are involved in different mechanisms of vascular growth (3, 4), and VEGF, in particular, plays a prominent role in activating endothelial cells to form new vessels (5). To date, much of the effort in therapeutic angiogenesis has been focused on the deliv- ery of VEGF to restore blood perfusion (6, 7). However, forma- tion of truly functional vasculature will likely require control over the location and magnitude of the angiogenic region. Undirected vessel growth can result in pathological effects (8), and impro- perly organized vascular networks resulting from this overstimu- lation can reduce perfusion (9, 10). This may be particularly problematic with angiogenic delivery approaches currently uti- lized, as systemic delivery leads to supraphysiologic concentra- tions, and even polymeric sustained delivery systems frequently demonstrate an early burst release that leads to oversaturated local VEGF concentration in situ (11). Importantly, although clearly documented with VEGF delivery, this issue permeates all current approaches to locally manipulate regenerative processes via exogenous factor delivery.
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Problem#3Mimicking nature by codelivery of stimulant and inhibitor

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