Nitric oxide releasing nanomatrix gel treatment inhibits venous intimal hyperplasia and improves vascular remodeling in a rodent arteriovenous fistula.

Vascular access is the lifeline for hemodialysis patients and the single most important component of the hemodialysis procedure. Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients, but nearly 60% of AVFs created fail to successfully mature due to early intimal hyperplasia development and poor outward remodeling. There are currently no therapies available to prevent AVF maturation failure. First, we showed the important regulatory role of nitric oxide (NO) on AVF development by demonstrating that intimal hyperplasia development was reduced in an overexpressed endothelial nitric oxide synthase (NOS3) mouse AVF model. This supported the rationale for the potential application of NO to the AVF. Thus, we developed a self-assembled NO releasing nanomatrix gel and applied it perivascularly at the arteriovenous anastomosis immediately following rat AVF creation to investigate its therapeutic effect on AVF development. We demonstrated that the NO releasing nanomatrix gel inhibited intimal hyperplasia formation (more than 70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress approaching the preoperative level and less vorticity). Therefore, direct application of the NO releasing nanomatrix gel to the AVF anastomosis immediately following AVF creation may enhance AVF development, thereby providing long-term and durable vascular access for hemodialysis.

Enhanced MIN-6 beta cell survival and function on a nitric oxide-releasing peptide amphiphile nanomatrix.

Innovative biomaterial strategies are required to improve islet cell retention, viability, and functionality, and thereby obtain clinically successful outcomes from pancreatic islet cell transplantation. To address this need, we have developed a peptide amphiphile-based nanomatrix that incorporates multifunctional bioactive cues and sustained release of nitric oxide. The goal of this study was to evaluate the effect of this peptide amphiphile nanomatrix on the viability and functionality of MIN-6 islet cells. Additionally, this study provides insight into the role of nitric oxide in islet cell biology, given that conventional nitric oxide donors are unable to release nitric oxide in a controlled, sustained manner, leading to ambiguous results. It was hypothesized that controlled nitric oxide release in synergy with multifunctional bioactive cues would promote islet cell viability and functionality. Nitric oxide-releasing peptide amphiphile nanomatrices within the range of 16.25 µmol to 130 µmol were used to analyze MIN-6 cell behavior. Both 32.5 µmol and 65 µmol peptide amphiphiles showed improved MIN-6 functionality in response to glucose over a 7-day time period, and the elevated functionality was correlated with both PDX-1 and insulin gene expression. Our results demonstrate that nitric oxide has a beneficial effect on MIN-6 cells in a concentration-dependent manner.