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Volume 69, Issue 12, Pages (June 2006)

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1 Volume 69, Issue 12, Pages 2179-2185 (June 2006)
Efficacy of local dipyridamole therapy in a porcine model of arteriovenous graft stenosis  T. Kuji, T. Masaki, K. Goteti, L. Li, S. Zhuplatov, C.M. Terry, W. Zhu, J.K. Leypoldt, R. Rathi, D.K. Blumenthal, S.E. Kern, A.K. Cheung  Kidney International  Volume 69, Issue 12, Pages (June 2006) DOI: /sj.ki Copyright © 2006 International Society of Nephrology Terms and Conditions

2 Figure 1 Histologic appearance of neointimal hyperplasia at the graft-venous anastomosis at different time points. The tissue cross-sections were obtained as described in Figure 7 (cross-section D) and stained with H&E and examined at original magnification, × 5. Neointimal hyperplasia (NH) was minimal at the graft-venous anastomosis at (a) 14 days and progressive at (b) 21 and (c) 28 days post-graft placement. Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions

3 Figure 2 Effect of local delivery of dipyridamole on neointimal hyperplasia at graft-venous anastomoses. Dipyridamole was delivered using microspheres/ReGel or ReGel alone as a perivascular sustained-release depot around the graft-venous and graft-arterial anastomoses as described in Table 1. The degree of neointimal hyperplasia was assessed by (a) visual scoring (scale of 0–5, with 5 representing maximal hyperplasia) and (b) by planimetry. The planimetry results are presented as the ratio of the cross-sectional surface area of the hyperplastic tissue, normalized to the cross-sectional surface area of the graft, resulting in a dimensionless value. The thin lines connecting the control and dipyridamole-treated values represent individual animals, whereas the thick line represents the median value of all animals. There were no statistically significant differences between the mean control values and the dipyridamole-treated values as assessed by either scoring (N=7; P=0.08) or planimetry (N=7; P=0.08). Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions

4 Figure 3 Effect of local delivery of dipyridamole on neointimal hyperplasia at graft-arterial anastomoses. The methods of drug administration and assessment of hyperplasia are similar to those described in Figure 2. (a) Results of visual scoring. (b) Results by planimetry. There were no statistically significant differences between the median control values and the dipyridamole-treated values at the graft-arterial anastomoses as assessed by either scoring (N=7; P=0.64) or planimetry (N=7; P=0.31). Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions

5 Figure 4 Histologic examination of a drug depot at the graft-vein anastomosis. Presented is the histologic cross-section stained with H&E at the graft-venous anastomosis of a graft that received dipyridamole in microspheres/ReGel intraoperatively and explanted after 28 days. The original magnification of the main figure is × 1. The drug depot was encapsulated with fibrous tissues, which was confirmed using trichrome staining (not shown). The inset (original magnification, × 20) is an enlargement of a segment of the depot, showing fibrous tissues surrounding the microspheres, infiltrated by mononuclear cells and giant cells (black arrow). Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions

6 Figure 5 Time-dependent changes in dipyridamole concentrations in venous and arterial walls at graft anastomoses. Dipyridamole (52 mg) was delivered using microspheres/ReGel as a perivascular sustained-release depot around the graft-venous and graft-arterial anastomoses. The graft and adjoining native vessels were explanted at the indicated time points after graft placement. Dipyridamole was extracted from the venous wall (a) and the arterial wall (b) and assayed. N=3 at 0.5, 1.5, 4, and 8 days and N=2 at 21 days. Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions

7 Figure 6 Photograph of ReGel mixed with dipyridamole-incorporated microspheres deposited at PTFE graft anastomoses. An arteriovenous PTFE graft was created between the common carotid artery and the external jugular vein. Liquid ReGel mixed with dipyridamole-incorporated microspheres was applied to the graft-arterial and the graft-veinous anastomoses (▴). This liquid transformed rapidly into a solid gel to provide a drug depot. The yellow color of the gel was imparted by dipyridamole. Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions

8 Figure 7 Cross-sections of the graft-vessel anastomoses for histologic analysis. Each graft-arterial or graft-veinous anastomosis was cut along the two dotted lines to produce cross-sections for histologic analysis of neointimal hyperplasia. The cross-section designated ‘P’ was standardized at 3 mm from the proximal edge, whereas the cross-section designated ‘D’ was standardized at 3 mm from the distal edge of the anastomosis. NH, neointimal hyperplasia. Kidney International  , DOI: ( /sj.ki ) Copyright © 2006 International Society of Nephrology Terms and Conditions


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