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Abstract
The clinical application of medical devices is complicated by cellular surface interactions, leading to device-induced thrombosis and infection. One emerging approach to combat these processes is the surface evolution of the gasotransmitter nitric oxide (NO), which mediates blood platelet quiescence and antibacterial effects. Despite efforts to develop NO-releasing (NOrel) surface technology, a grand challenge remains in improving the paradigm for clinical translation and commercialization.
NO is but a single mediator of reactive oxygen/nitrogen/sulfur species (ROS/RNS/RSS), undergoing several key interactions with other endogenous species. In this dissertation work, novel strategies to modulate gasotransmitter elution and redox processes are developed for the direction of localized biological effects. In the first approach, controlled release technologies are developed for NO using metal-organic frameworks (Chapter 2), covalent immobilization strategies with carbon nanomaterials (Chapter 5), and hydrogels (Chapter 6). These combination technologies and design strategies are shown to facilitate tunable NO release profiles across physiological interfaces, promoting antibacterial effects while enabling mammalian cell proliferation.
In the second approach, exploratory technologies with ROS/RNS/RSS species are investigated using a dual-ROS strategy with NO and hydrogen peroxide (H2O2, Chapter 3) and development of novel RSS-evolving biomaterials through hydrogen sulfide (H2S, Chapter 4). Dual-ROS strategies are achieved via the development of redox cycling on NOrel substrates, enabling ROS interaction and diversification. RSS strategies are developed by integrating a H2S donor into bulk medical-grade polymers, showcasing tunable H2S release profiles based on formulation constraints and enabling diverse cellular proliferative and antiplatelet effects.
In a third approach, dual bioactive/biopassive strategies are investigated with NO. In Chapter 7, NOrel surfaces are combined with heparin to achieve a dual antiplatelet/anticoagulant strategy, showcasing improved antithrombotic effects. In Chapter 8, metal-polyphenol surfaces are investigated for NO catalysis and antifouling performance at the polymer-fluid interface. In Chapter 9, highly antimicrobial and antithrombotic hydrophilic NOrel materials are developed and evaluated in in vivo models of extracorporeal circulation.
The novel strategies for reactive species evolution and surface passivation are shown to improve therapeutic efficacy compared to several existing NO-releasing strategies, showcasing the potential to reduce device-associated infection and thrombosis through highly translatable fabrication strategies.
NO is but a single mediator of reactive oxygen/nitrogen/sulfur species (ROS/RNS/RSS), undergoing several key interactions with other endogenous species. In this dissertation work, novel strategies to modulate gasotransmitter elution and redox processes are developed for the direction of localized biological effects. In the first approach, controlled release technologies are developed for NO using metal-organic frameworks (Chapter 2), covalent immobilization strategies with carbon nanomaterials (Chapter 5), and hydrogels (Chapter 6). These combination technologies and design strategies are shown to facilitate tunable NO release profiles across physiological interfaces, promoting antibacterial effects while enabling mammalian cell proliferation.
In the second approach, exploratory technologies with ROS/RNS/RSS species are investigated using a dual-ROS strategy with NO and hydrogen peroxide (H2O2, Chapter 3) and development of novel RSS-evolving biomaterials through hydrogen sulfide (H2S, Chapter 4). Dual-ROS strategies are achieved via the development of redox cycling on NOrel substrates, enabling ROS interaction and diversification. RSS strategies are developed by integrating a H2S donor into bulk medical-grade polymers, showcasing tunable H2S release profiles based on formulation constraints and enabling diverse cellular proliferative and antiplatelet effects.
In a third approach, dual bioactive/biopassive strategies are investigated with NO. In Chapter 7, NOrel surfaces are combined with heparin to achieve a dual antiplatelet/anticoagulant strategy, showcasing improved antithrombotic effects. In Chapter 8, metal-polyphenol surfaces are investigated for NO catalysis and antifouling performance at the polymer-fluid interface. In Chapter 9, highly antimicrobial and antithrombotic hydrophilic NOrel materials are developed and evaluated in in vivo models of extracorporeal circulation.
The novel strategies for reactive species evolution and surface passivation are shown to improve therapeutic efficacy compared to several existing NO-releasing strategies, showcasing the potential to reduce device-associated infection and thrombosis through highly translatable fabrication strategies.