Problem#3Mimicking nature by codelivery of stimulant and inhibitor

Encapsulated vegf and ava scaffolds effectively

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Unformatted text preview: scaffolds effectively restricted this increase to the muscle directly underneath the central layer (Fig. 4). Histologic analysis demonstrated no other detectable differences in the surrounding muscular tissues exposed to anti-VEGF antibody, as compared to the blank control conditions (Fig. S7). Additional analysis (Fig. S8) also demonstrated the development of the spatially restricted angiogenic zone at week 1 and week 2 for both the implanted scaffold and the underlying muscle. Finally, LDPI was performed in order to assess the effects on functional perfusion by local restriction of angiogenesis (Fig. 5). In all groups, perfusion decreased immediately subsequent to induction of ischemia. However, implantation of all three types of scaffolds containing VEGF led to significant recovery of perfusion, well above the control (no VEGF delivery), and spatially restricting angiogenesis did not compromise the ability of VEGF delivery to improve regional perfusion. Necrosis in the limbs was also analyzed (Fig. S9); the AVA scaffold was demonstrated to lead to moderate prevention of necrosis as compared to the control BVB scaffolds. Discussion The results from these studies demonstrated that one can spatially control regenerative processes by simultaneously delivering spatially segregated promoting and inhibitory agents with polymeric scaffolds. More specifically, the simultaneous, but spatially distinct, delivery of anti-VEGF and VEGF reduced the initial burst concentration of active VEGF and maintained the temporal stability of the active VEGF concentration profile. Furthermore, the spatial separation of the encapsulated pro- and antiangiogenic agents resulted in a spatially sharp and restricted angiogenic region, leading to a heterogeneous distribution of vessels in the scaffolds and in underlying muscles. The in vitro sprouting assay from this study confirmed that the anti-VEGF was functional and inhibited angiogenesis in a PNAS ∣ October 19, 2010 ∣ vol. 107 ∣ no. 42 ∣ 17935 APPLIED BIOLOGICAL SCIENCES profiles in vivo that were published previously (11). Predicted concentrations were comparable to the experimental results (see Fig. S3). In the layered AVA scaffolds in this study, an initial amount of 4 μg VEGF was encapsulated in the central layer of the scaffold, and 20 μg anti-VEGF was encapsulated in each of the surrounding layers (Fig. 2A). For these scaffolds, the concentration profiles of total VEGF, free VEGF (not bound to anti-VEGF), and free anti-VEGF over time at a tissue cross-section 0.5 mm into the underlying muscle were simulated (Fig. 2 B–D). These simulations showed a sharp peak for the total VEGF concentration (free VEGF þ VEGF bound to antibody) centered at the central layer and two anti-VEGF peaks on the two sides. However, the diffusion of anti-VEGF into the central layer caused most of the total VEGF to become bound to antibody in the central layer, creating significantly reduced peaks of free VEGF compared to total VE...
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