Problem#3Mimicking nature by codelivery of stimulant and inhibitor

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Unformatted text preview: mL . fined as Sðx;y;zÞ ¼ 0 for ½VEGFf Š ≤ 5 ng∕mL 17936 ∣ www.pnas.org/cgi/doi/10.1073/pnas.1001192107 Yuen et al. APPLIED BIOLOGICAL SCIENCES Fig. 3. Blood vessel densities within layered scaffolds 4-wk postimplantation (n ¼ 5). Representative images (A) of CD31 stained sections of various types of scaffolds implanted in ischemic hind limbs. B only, blank scaffolds; V only, scaffolds delivering only VEGF; BVB, trilayered scaffolds with a VEGF-containing layer sandwiched by two blank layers; AVA, trilayered scaffolds with a VEGF-containing layer sandwiched by two anti-VEGF-containing layers. Scale bar represents 200 μm. Quantification of vessel densities (B) within each layer of implanted scaffolds (*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001). Values represent mean, and error bars represent standard deviations (n ¼ 5). dose-dependent manner. These findings were consistent with a previously reported ND50 of 4 to 15 times the mass of VEGF (30). The release profiles of VEGF and its antibody showed that the two agents were released in a sustained manner, albeit with initial bursts as observed in other studies utilizing poly(lactic-coglycolic acid) (32, 33). By simultaneously delivering anti-VEGF with VEGF in AVA scaffolds, the overly high concentration of VEGF that typically results from the initial burst release was mitigated. Computational simulations accounting for release, diffusion, degradation, and binding dynamics of VEGF and anti-VEGF showed that excessive VEGF was bound by anti-VEGF in this situation. The remaining free VEGF is the only active angiogenic agent delivered. Because release profiles of VEGF and anti-VEGF both exhibit initial bursts, the resulting concentration profile peak of free VEGF in the beginning was drastically reduced. Thus, a temporally stable concentration profile of an active angiogenic agent is achieved with a delivery device that has an inherent initial burst release. This methodology can also likely be applied to other drug delivery applications in order to mitigate the negative effects of initial bursts. The capillary densities achieved in VEGFYuen et al. Fig. 4. Blood vessel densities within muscle tissue sections (n ¼ 5) directly underneath the corresponding scaffold layer. Representative images (A) of CD31 stained muscle sections directly underneath the layers of various types of implanted scaffolds. Scale bar represents 200 μm. Quantification of vessel densities (B) within the underlying muscles (*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001). Values represent mean and error bars represent standard deviations (n ¼ 5). Fig. 5. Quantitative analyses of hind-limb perfusion using LDPI in mice (n ¼ 5). Blood flow was expressed as ischemic limb/untreated limb perfusion in mice. B, blank scaffolds; V, scaffolds delivering only VEGF; BVB, trilayered scaffolds with a VEGF-containing layer sandwiched by two blank layers; AVA, trilayered scaffolds. Implantations of scaffolds containing VEGF (V, AVA, BVB) all result...
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This document was uploaded on 09/21/2013.

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