Problem#3Mimicking nature by codelivery of stimulant and inhibitor

Of free vegf compared to total vegf fig 2e strikingly

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Unformatted text preview: GF (Fig. 2E). Strikingly, the binding of free VEGF by antibody had a dramatic smoothing effect on the concentration of free VEGF as a function of time. In contrast, the total VEGF concentration started extremely high and then rapidly dropped, due to the changing release rate over time and its simultaneous degradation. These effects were largely doseindependent (Figs. S4 and S5), although the absolute value of the quasi-steady-state free-VEGF concentration was strongly influenced by the VEGF and anti-VEGF doses. From previous in vitro VEGF dosage studies of endothelial sprouting (29) and in vivo measurement of tissue VEGF concentrations (11), the minimum effective VEGF concentration in vivo to induce angiogenesis is ∼5 ng∕mL. As shown by the computational model, utilization of the 4-μg doses led to free-VEGF concentrations that were still above this threshold for a 3-wk time frame. In addition, as a comparison of the profile stability, the standard deviations of the daily peak for total VEGF and free VEGF over 28 d were computed: 558 ng∕mL for total VEGF and 132 ng∕mL for free VEGF. Most of the fluctuations came from the spike in concentrations on day 2 (Fig. 2G). The concentration peak of active VEGF on day 2 was reduced by 72% by the binding activity of anti-VEGF. To determine the spatial control over angiogenesis with this approach, the level of angiogenic promotion was expressed as a binary event, defined as angiogenic promotion signal (S), Fig. 2. Results from computational simulation of an AVA implanted scaffold. (A) Orientation of implanted scaffold in a mouse that underwent ischemic hind-limb surgery. The orientation of the scaffold was chosen to create an angiogenic zone directly over the section of the femoral artery that was ligated—with a goal of creating new blood vessels that would bypass the ligated vessel. The spatially restricted APR was designed to limit angiogenesis in other limb regions that presumably would not provide perfusion recovery function. The axes definitions are such that x is perpendicular to the severed femoral artery and vein, y is parallel to the femoral artery and vein, and positive z points away from the underlying muscle. Note that the x -y plane lies tangential to the interface between the scaffold and the underlying muscle, and that the coordinate (0,0,2.1 mm) is located at the center of the scaffold. Simulation results of the concentration profiles of (B) total VEGF, (C) free VEGF, and (D) free anti-VEGF over time at y ¼ 0 and z ¼ −0.5 mm. (E) Cross-sectional plots of concentration profiles of total anti-VEGF (blue solid) and free anti-VEGF (green dashed) at 3, 7, 14, and 21 d. (F) Cross-sectional plots of concentration profiles of total VEGF (blue solid) and free VEGF (green dashed) at 3, 7, 14, and 21 d. (G) The maximum concentrations of total VEGF and free VEGF over time. (H) APR at 1, 7, and 14 d for AVA (Left) and BVB (Right). The angiogenic promotion signal is de 1 for ½VEGFf Š > 5 ng...
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