Project Summary Thrombosis and infection are major deterrents to positive health outcomes in hospital patients with long-term stays. Methods to improve these outcomes and reduce the possibility of bloodborne infection for stays up to and beyond 30 days are highly sought after. Over the years a series of active nitric oxide (NO) releasing and generating materials have been incorporated into medical devices to aid in blood clot and infection reduction; however, there are significant limitations with the designs of NO release (NOrel) materials in that most do not offer a very good and sustained NO flux over long periods of time, leading to inadvertent infections or needing constant swap outs. Due to this, we propose the development of polymeric materials that will reduce thrombosis by mimicking the endothelium via inhibition of platelet adhesion/activation and preventing microbial infections. We will use silicon-oxygen, 3D-cage structures (silsesquioxanes) modified with S-nitroso-N-acetylpenicillamine (SNAP), a biocompatible NO-donor, and anchored as pendant groups on silicone rubber polymers. These pendant cages will offer strong interactions between NO-release groups and blood fluids leading to sustained NOrel fluxes. We hypothesize that the pendant SNAP-3D cage NO release polymers will offer better sustained NO flux over previous NOrel polymers due to their excellent biocompatibility, a much higher density of NO release groups (~8 NO/nm3) than direct surface functionalization, and their very modifiable structures for polarity/steric adaptations. To test this hypothesis, we propose two specific aims. The first aim is to develop SNAP functionalized silsesquioxanes as pendent NO-release agents on silicone rubber polymers (PDMS) to enhance and control NOrel capabilities. We will use thiol-ene chemistries to covalently graft the silsesquioxanes onto PDMS, and then load them with NO before testing. The NOrel polymers will then be tested for NO-release properties, physical/mechanical properties, durability, leaching, and storage/sterilization stability. Their ability to mimic the higher range of NO flux exhibited by endothelial cells (2-4 x 10-10 mol cm-2 min-1) and for the polymer materials to achieve activity for up to 30 d under physiological conditions will be tested and documented. The second aim will evaluate the synergistic effects of the NOrel polymers on platelet adhesion and bacterial infection using in vitro bioassays for verifying polymer NO-release and compatibility in biological systems. These polymers will be studied for their ability to inhibit access to GPIIb/IIIa fibrinogen receptors using NO as a platelet anticoagulant agent with in vitro bioassay methods. The antimicrobial effects will be evaluated in vitro (bioreactor) with common bloodborne pathogens associated with indwelling medical devices which lead to bloodstream infections (i.e. Pseudomonas aeruginosa). We expect the proposed NO-release polymers to meet or exceed our expected NO flux of 2-4 x 10-10 mol cm-2 min-1 over 30 days and offer effective biocidal and anticoagulant properties. This research will have profound impact on reducing negative health consequences of blood clotting and infection of long-stay ICU patients and enable faster recovery from their primary ailments.

Project Narrative Medical devices are useful tools that have served to prevent and cure illnesses; however, they often lead to inadvertent health effects due to harboring and promoting growth of bacteria/viruses, and their low compatibility with components within the body. We present new methods towards a set of biocompatible silicon-based materials for medical devices such as catheters that enable long-term and controlled release nitric oxide as an anti-infection and anti-blood clotting agent. This research will establish an enhanced route to improve the health outcomes of ICU hospital patients by reducing hospital aquired infections and blood clotting that can lead to disability, death, and/or longer recovery times from primary afflictions.