Nitric oxide generation from S-nitrosothiols via interactivity with polymer-supported metal-organic frameworks
Date
2018
Authors
Neufeld, Megan J., author
Reynolds, Melissa, advisor
Chen, Eugene, committee member
Finke, Richard, committee member
Kipper, Matthew, committee member
Ravishankara, A. R., committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Catheters, extracorporeal systems, stents, and artificial heart valves are all common blood-contacting medical devices. Due to the differences in the chemical and physical properties of the polymeric materials used to construct medical devices and biological tissues in the cardiovascular system, complications such as thrombus formation arise from the resulting incompatibilities. Introduction of foreign materials that lack critical biological cues can result in disruption of the delicate balance maintained within the circulatory system. This disruption of homeostasis initiates a complex cascade of events such as platelet adhesion and protein deposition that ultimately result in thrombus formation. As such, the propensity of blood to clot upon contact with a foreign surface represents a challenge unique to devices intended for vascular applications. The current clinical use of devices such as vascular catheters includes the administration of anticoagulants, however their associated complications such as internal hemorrhaging renders this practice undesirable as a long-lasting solution. A general limitation of existing devices made from synthetic polymers is their inability to integrate with their environment through biological cues (natural regulators). Materials that lack this behavior are often described as passive towards their environment. In comparison, active materials that can simulate natural molecules used to maintain biological responses may result in enhanced integration of medical devices. In the natural, healthy endothelium, the prevention of thrombus formation occurs through the release of anticoagulants and platelet inhibitors such as gaseous nitric oxide (NO). While the use of NO for medicinal purposes began indirectly in the late 1800s, the significance of its endogenous production was not known until the 1970s. In particular, NO is a key factor in the prevention of thrombus formation. While its remedial potential has led to its use as an exogenous therapeutic agent, its high reactivity limits its applicability as a localized therapeutic. This limitation is addressed by mimicking the natural endothelium and using small molecules in the bloodstream known as S-nitrosothiols (RSNOs) to produce NO directly from this physiological source. Biological RSNOs are theorized to aid in the stabilization and transport of NO and undergo an NO-forming decomposition in the presence of heat, light, and certain metals such as copper. Prior strategies have evaluated exploiting the physiological supply of RSNOs through the incorporation of copper complexes into polymeric materials. While these copper-based materials demonstrate the production of NO from RSNO decomposition, limitations arise due to the gradual loss of the catalytic material and toxicity from copper leaching. In order for this type of approach to be feasible, the active metal species must remain immobilized within the structural framework. Metal–organic frameworks (MOFs) are a class of crystalline materials that consist of organic ligands coordinated to metal centers. Certain copper-based MOFs have demonstrated the ability to enhance the generation of NO from RSNOs without the gradual loss of the active species. Through integration of certain copper-based MOFs with medically relevant polymers, materials can be prepared that promote the localized generation of NO at their surfaces. However, the feasibility of utilizing copper-based MOFs for such applications depends on effective incorporation within a supporting polymeric matrix and the retention of useful activity thereafter. As such, it is necessary to assess different MOF/polymer composites for their ability to promote NO generation from RSNOs prior to use in medical applications. This dissertation investigates the incorporation of two distinct copper-based MOFs into a selection of medically-relevant polymeric materials including cotton, poly(vinyl chloride), chitosan, and poly(vinyl alcohol). These MOF/polymer materials were subsequently tested for their ability to promote NO generation from RSNOs in an effort to assess the impact of incorporation within a polymer matrix. Overall, this work demonstrates the potential for blood-contacting MOF-containing materials in biomedical settings by identifying ideal characteristics that MOF/polymer composites should exhibit for optimization and translation to a clinical setting.
Description
Rights Access
Subject
metal-organic frameworks
S-nitrosothiols
nitric oxide
blood-material interactions