BIOINSPIRED INFECTION AND THROMBOSIS-RESISTANT FUNCTIONAL BIOMATERIALS

Advanced biomedical devices have revolutionized healthcare and have significantly improved patient mortality, morbidity, and standard of care. These medical devices are often challenged with infections and thrombus formation during the application. These complications severely impact the treatment outcome leading to increased device failure, and extended hospital stay and could be lethal. Nitric oxide (NO), an endogenously produced gasotransmitter with potent anti-bacterial and anti-thrombotic properties has gathered immense interest as a tool to design infection and thrombosis-resistant biomaterials. Various NO donors have been developed and incorporated into medical-grade polymers and have shown promising antibacterial and hemocompatible behavior in vitro and in vivo. However, these materials have a few shortcomings including limited NO donor reservoir, uncontrolled evolution of NO, biofouling, and inefficacy towards fungal infections.In this dissertation work, NO-releasing materials were combined with various bioactive or passive strategies to design medical-grade polymeric composites with versatile biomedical applications. In the first approach (Chapter 2), NO donor S-nitroso-N-acetylpenicillamine (SNAP) incorporated low water uptake polycarbonate urethane was functionalized with anti- fouling high water uptake polyether urethane interface containing anti-fungal drug fluconazole. The design allowed for controlled tunable release of NO and fluconazole from the polymeric composites under physiological conditions. The resulting composites showed potent antimicrobial activity against clinically relevant Staphylococcus aureus, Escherichia coli, and Candida albicans (>90% reduction in both adhered and planktonic microbial load). In the second approach (Chapter 3), medical-grade plasticized PVC was impregnated with SNAP and surface functionalized with antibacterial polyethyleneimine and anti-biofilm agent N-acetyl cysteine. The resulting composites showed extended, controlled release of NO under physiological conditions. The composites also demonstrated >95% reduction of S. aureus and E. coli in both adhered and planktonic forms. A significant reduction of bacterial load (>90%) and biomass accumulation (>65%) was obtained in a 72-h drip flow bioreactor setup. In the third approach (Chapter 4), a passive surface functionalization was employed to design an anti-fouling interface. The base polymer PVC was impregnated with SNAP to induce NO-releasing properties. The designed polymeric interface showed tunable NO release and enhanced surface wettability resulting in significant protein-repelling, anti-biofouling, antibacterial, and anti-platelet properties while maintaining biocompatibility. The polymeric interface also significantly prevented biofilm accumulation on the surface, tested in a drip flow bioreactor over 72-h. The fourth approach was designing a novel water-soluble NO donor called S-nitroso polyethyleneimine (PEI-SNAP) which combined the broad spectrum potent anti-bacterial and anti-fungal capabilities of PEI with cytocompatibility and cell proliferative effects of NO (Chapter 4). The potential applications of this NO donor for fabricating NO-releasing polymeric interfaces and catheter lock solutions are discussed in Chapters 6 and 7. The combinatorial bioactive and passive strategies explored in this dissertation significantly improved the bioactivity of NO-releasing technology in preventing infections and thrombosis. These approaches hold the potential for designing bioinspired polymeric interfaces, that can cater to a wide range of biomedical applications in clinical settings.

INDEX WORDS: Nitric oxide, Anti-microbial, Hemocompatible, Antibiotic-resistance, Anti-fouling, Bioinspired.