Tissue Integration and Antimicrobial Effects of Surface-derived Nitric Oxide Release

Nichols, Scott Philip

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March 22, 2019

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Nichols, Scott Philip
- Affiliation: College of Arts and Sciences, Department of Chemistry

Abstract

The analytical performance of glucose sensors is inhibited by the host’s foreign body response (FBR) and risk of bacterial infection. To date, no one strategy has circumvented the physiological reactions to implanted materials. Nitric oxide (NO) is an endogenously produced free radical that acts to initiate events in the FBR and fight bacterial infection. Herein, the potential of NO-releasing surfaces to both mitigate the FBR and bacterial invasion is described. Evaluation of the performance of NO-releasing surfaces to improve glucose sensor performance in vivo was carried out through imparting NO release to microdialysis probes. Perfusion of saturated NO solutions through implanted probes delivered a constant flux of 162 pmol cm-2 s-1 delivering 4.6 μmol cm-2 NO each day. The NO-releasing probes recovered significantly greater concentrations of glucose after 7 d of implantation versus controls. Histological analysis revealed a thinner collagen capsule and decreased inflammation adjacent to NO-releasing probes. To investigate the necessary NO-release properties to achieve the observed histological benefits, NO-releasing polyurethane-coated wires were implanted into a porcine model for up to 6 weeks. Polyurethanes were doped with small molecules or nanoparticles to alter the NO release kinetics, fluxes, and total payloads. Materials with a NO-release duration of 14 d and large NO payload (9.3 μmol cm-2) were most effective at decreasing the collagen encapsulation and inflammation adjacent to the implants. Inflammation was only modulated during active NO release from the implant. While modulation of the FBR is essential for the development of glucose sensors, infection by bacteria is a constant threat. Biomaterial-associated infections most commonly begin through adhesion to the implanted material. Therefore, evaluation of the anti-adhesive properties of NO-releasing surfaces was undertaken by examining the adhesion of six bacterial strains to a wide range of NO fluxes (0.5–50 pmol cm-2 s-1). An average NO flux between 50 pmol cm-2 s-1 reduced surface coverage of all strains by >80% over 1 h. Further, after incubation of adhered bacteria in bacteriostatic conditions for 24 h, large surfacederived NO payloads (1.7 μmol cm-2) decreased viability of adhered bacteria by ≥85%.

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