(B-63) Application of Nitric Oxide Releasing Bionanomatrix Gel For Dialysis Arteriovenous Fistula Maturation

Introduction:: About 600,000 patients in the US suffer from end-stage renal disease (ESRD); more than 75% of ESRD patients undergo dialysis. Vascular access dysfunction is a major cause of morbidity and hospitalization in dialysis patients. Arteriovenous fistulas (AVFs) are considered the gold standard of vascular access for dialysis. However, about 60% of AVFs fail to mature because of early venous neointimal development and poor vasodilation and vascular wall remodeling. Therefore, to promote AVF maturation, we propose the application of a nitric oxide (NO) releasing nanomatrix gel, or ‘NO gel’, on the created AVF. The NO gel is composed of peptide amphiphiles (PA), which contain an endothelial cell adhesive ligand (YIGSR) and a polylysine (KKKKK) group to form NO-donating residues. The NO gel releases NO over a one-month period, promotes vasodilation of the AVF during maturation, inhibits smooth muscle cell proliferation, and reduces inflammation. In this study, we test our hypothesis that the NO gel applied at AVF creation can promote AVF maturation by decreasing venous intimal hyperplasia, enhancing vasodilation and vascular outward remodeling, and improving endothelial function.


Materials and Methods:: To create the gel components, PAs with YIGSR or KKKKK were synthesized and mixed in a 9:1 molar ratio (M_R) to form ‘PA-YK’. PA-YK was charged with NO to produce PA-YK-NO. The NO gel was created by combination of 1:1 M_R of PA-YK-NO and PA-S (without YIGSR or KKKKK). For in vivo studies, AVFs in rats were created by connecting the femoral vein to the artery. The NO gel was applied at the AVF anastomosis site for 7 days. AVF hemodynamics were evaluated using MRI-based computed fluid dynamics (CFD) analysis. The rats were sacrificed after 7 days; collected AVFs underwent histology and immunohistochemistry analysis to examine intimal hyperplasia development (Fig.1). AVFs were also created in a porcine model by creating an end-to-side anastomosis of the internal jugular vein and carotid artery. The NO gel was applied at the porcine AVF anastomosis site for 35 days. AVF diameter and blood flow was characterized by ultrasound and color doppler ultrasound, respectively.


Results, Conclusions, and Discussions:: The NO gel demonstrated an initial burst release of NO at 48 hours to arrest neointimal hyperplasia, followed by sustained release over 28 days to aid AVF maturation. The NO gel treatment inhibited intimal hyperplasia formation ( >70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress and vorticity) of rat AVFs after 7 days. Furthermore, the NO gel also significantly improved hemodynamics and vascular remodeling of porcine AVFs compared to the control AVF after 35 days.

Conclusion: These results indicate that our NO gel application on AVFs has great potential to promote AVF maturation by reduction of intimal hyperplasia and improvement of vascular outward remodeling and hemodynamics in both small (rat) and large (porcine) animal AVF models. Thus, we expect that the NO gel will enhance dialysis vascular access clinically.


Acknowledgements (Optional): : This project was supported by the grant of NIH 2R44DK109789-01, -02, and -04. NIH 1R01HL139692 and 1R01HL163802.


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