Problem#3Mimicking nature by codelivery of stimulant and inhibitor

Then contracted slowly in the first 19 d the apr

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Unformatted text preview: the first 19 d, the APR width expanded gradually from 0.84 mm to 1.2 mm, although there is a brief drop to 0.48 mm on day 4. From day 20 to day 28, the APR contracted from 1.2 mm to 0.72 mm. Compared to the sole delivery of VEGF, the codelivery of VEGF and anti-VEGF showed improved ability to constrict the width of APR (Fig. 2H). In this computational model, 5 ng∕mL was chosen as the minimum threshold for angiogenic promotion, consistent with other groups (30, 31). The choice of this parameter did not affect the temporal stability of the free-VEGF concentration profiles, though the width of the APR deviated by Æ25% with the minimum threshold ranging from 2 ng∕mL to 10 ng∕mL (Fig. S6). Thus, both temporal stability and spatial restriction of active VEGF were robust to the minimum biologically active threshold. The results of this modeling suggest that highly stable, in terms of both time and space, regions of proangiogenic Yuen et al. activity could be readily created by appropriate dosing of VEGF and anti-VEGF. The maintenance of the APR is also robust against changes in the amount of anti-VEGF and VEGF encapsulated initially. When the initial encapsulated mass of antiVEGF was varied from 80% to 110% of the base level, the width of the APR deviates for less than 25% (Fig. S4). Similarly, the width of the APR deviated for less than 25% when the degradation rate of anti-VEGF was varied from 80% to 130% (Fig. S5). Spatially Regulated Angiogenesis in Vivo. To test the ability of this system to provide spatial control over angiogenesis, scaffolds were subsequently implanted into the ischemic hind limbs of SCID mice. Both the vasculature that formed within the infiltrated scaffold and the vasculature in the muscle underneath the scaffold were analyzed. To this end, four types of scaffolds were examined: (i) B, (ii) V, (iii) AVA, and (iv) BVB. The aforementioned computational model suggested that implanted AVA scaffolds would result in a distinct region that promoted angiogenesis and that this region would be maintained in the first two weeks. This spatially restricted signal was expected to lead to spatially heterogeneous blood vessel densities. At the experimental end point (4 wk), mice were sacrificed and blood vessel densities of the cell-infiltrated scaffolds and underlying muscles were quantified. Delivery of VEGF in all scaffold types (V, BVB, and AVA) resulted in an approximate twofold increase in blood vessel density in the scaffolds (Fig. 3 A and B). Furthermore, layers “B” in BVB showed a similar level of increase (Fig. 3B), indicating that the region of angiogenesis promotion was not restricted to the central layer. In contrast, layers “A” in the AVA scaffolds showed a reduction of blood vessel density, to a similar value as the blank condition (Fig. 3B). Similarly, analysis of the underlying muscle showed that increased blood vessel densities were generated in the muscles underneath a polymer initially encapsulated VEGF, and AVA...
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This document was uploaded on 09/21/2013.

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