Browsing by Author "Reynolds, Melissa, advisor"
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Item Open Access A selection of nitric oxide-releasing materials incorporating S-nitrosothiols(Colorado State University. Libraries, 2017) Lutzke, Alec, author; Reynolds, Melissa, advisor; Henry, Charles, committee member; Kennan, Alan, committee member; Kipper, Matthew, committee memberNitric oxide (NO) is a diatomic radical that occurs as a crucial component of mammalian biochemistry. As a signaling molecule, NO participates in the regulation of vascular tone and maintains the natural antithrombotic function of the healthy endothelium. Furthermore, NO is produced by phagocytes as part of the immune response, and exhibits both antimicrobial and wound-healing effects. In combination, these beneficial properties have led to the use of exogenous NO as a multifunctional therapeutic agent. However, the comparatively short half-life of NO under physiological conditions often renders systemic administration infeasible. This limitation is addressed by the use of NO-releasing polymeric materials, which permit the localized delivery of NO directly at the intended site of action. Such polymers have been utilized in the development of antithrombotic or antibacterial materials for biointerfacial applications, including tissue engineering and the fabrication of medical devices. NO release from polymers has most frequently been achieved through the incorporation of functional groups that are susceptible to NO-forming chemical decomposition in response to appropriate environmental stimuli. While numerous synthetic sources of NO are known, the S-nitrosothiol (RSNO) functional group occurs naturally in the form of S-nitrosocysteine residues in both proteins and small molecule species such as S-nitrosoglutathione. RSNOs are synthesized directly from thiol precursors, and their NO-forming decay has generally been established to produce the corresponding disulfide as a relatively benign organic byproduct. For these reasons, RSNOs have been conscripted as practical NO donors within a physiological environment. This dissertation describes the synthesis and characterization of RSNO-based NO-releasing polymers derived from the polysaccharides chitin and chitosan, as well as the development of amino acid ester-based NO-releasing biodegradable poly(organophosphazenes) (POPs). The broad use of chitin and chitosan in the development of materials for tissue engineering and wound treatment results in a significant overlap with the therapeutic properties of NO. NO-releasing derivatives of chitin and chitosan were prepared through partial substitution of the carbohydrate hydroxyl groups with the symmetrical dithiols 1,2-ethanedithiol, 1,3-propanedithiol, and 1,6-hexanedithiol, followed by S-nitrosation. Similarly, thiol-bearing polyphosphazenes were synthesized and used to produce NO-releasing variants. Polyphosphazenes are a unique polymer class possessing an inorganic backbone composed of alternating phosphorus and nitrogen atoms, and hydrolytically-sensitive POP derivatives with organic substituents have been prepared with distinctive physical and chemical properties. Although POPs have been evaluated as biomaterials, their potential as NO release platforms has not been previous explored. This work describes the development of NO-releasing biodegradable POPs derived from both the ethyl ester of L-cysteine and the 3-mercapto-3-methylbutyl ester of glycine. The NO release properties of all polymers were evaluated at physiological temperature and pH, and the results suggested potential suitability in future biomaterials applications.Item Open Access Adsorptive separations of phytocannabinoids and pesticides in the liquid phase(Colorado State University. Libraries, 2022) Cuchiaro, Jamie H., author; Reynolds, Melissa, advisor; Farmer, Delphine, committee member; Chung, Jean, committee member; Reardon, Ken, committee memberTo view the abstract, please see the full text of the document.Item Open Access An investigation of the effect of surface released nitric oxide on fibrinogen adsorption(Colorado State University. Libraries, 2014) Lantvit, Sarah Marie, author; Reynolds, Melissa, advisor; Borch, Thomas, committee member; Fisher, Ellen, committee member; Kennan, Alan, committee member; Popat, Ketul, committee memberThe search for improved biomaterials is a continually ongoing effort to prevent the failure of medical devices due to blood clotting. Each group of researchers has their own set of methods to create the ideal material for biological systems. In the pursuit of materials to prevent blood clot formation, these attempts have been focused on alterations in surface properties, pre-adsorption of proteins, and release of drugs. In this work I took a high-throughput approach to the prevention of device failure by investigating a model material system. Starting with a nitric oxide (NO) releasing material, a sample preparation method was developed to ensure that surface properties could be compared to a non-NO releasing control. With this material, the effect of the NO release on fibrinogen adsorption to these surfaces could be isolated. Fibrinogen is instrumental in the formation of blood clots. Determining the effect that NO has on this protein will help determine why NO has been previously found to prevent clotting in blood-contacting systems. Once the model system was developed, further investigation into changes in the fibrinogen resulting from its interaction with the released NO could be undertaken. A full investigation was completed on control non-NO releasing, low NO flux, and high NO flux materials. A qualitative assessment of the fibrinogen adsorption shows that the high NO releasing material exhibits significantly higher fibrinogen adsorption compared to both the control and low NO flux materials. Quantitative assessment of fibrinogen adsorption was attempted through a variety of methods, which indicate that conformational changes are happening upon adsorption of fibrinogen to all materials. To this end, FTIR spectra from the adsorbed fibrinogen and native fibrinogen were compared to elucidate changes in the protein's conformation. Control and low NO flux materials had too little protein to gain insight into these changes. For the high NO flux material, the fibrinogen had a significant decrease in α-helices and an increase in random chains compared to native fibrinogen. To begin understanding the effect that these changes will have on blood clot formation, these materials were further analyzed for platelet adhesion. A comparison of the control, low NO flux, and high NO flux materials with and without fibrinogen adsorbed to the material surface shows that the fibrinogen has a distinct effect on platelet adhesion and aggregation. The high NO flux materials exhibited less aggregation and full activation of platelets when fibrinogen was adsorbed prior to incubation with platelets than if fibrinogen was not present before incubation. Overall, the effect of NO on fibrinogen adsorption can be seen through these measurements. Nitric oxide release causes an increase in fibrinogen adsorption, as well as protein reorganization. Surprisingly, we see that this adsorbed fibrinogen actually improves the viability of platelets. Further study must be done using whole blood and in vivo measurements to fully understand what effect the adsorbed fibrinogen will have on the device. Despite this we can say that the adsorption of fibrinogen onto these NO releasing materials helps to improve the biocompatibility of this biomaterial due to its bulk adsorption and conformational changes.Item Open Access Anticancer potential of nitric oxide-based therapeutics for pediatric and adult cancers(Colorado State University. Libraries, 2021) Gordon, Jenna Leigh, author; Reynolds, Melissa, advisor; Henry, Chuck, committee member; Kennan, Alan, committee member; Brown, Mark, committee memberBased on 2015-2017 data, nearly 40% of men and women will be diagnosed with cancer at some point throughout their lives. As a worldwide pandemic, cancer presents a colossal challenge for researchers and clinicians to continually develop and implement new strategies to prevent, diagnose, and treat the many variations of this disease. Currently, treatment protocols are dominated by surgery, chemotherapy, and radiation therapy. Although valuable, these treatments are often ineffective and are limited to specific situations. Surgery is typically useful for early-stage cancer treatment while chemotherapy and radiation therapy are more common for late-stage treatment. Chemotherapy and radiation therapies are subject to drug resistance and all three produce patient side effects. Thus, a persistent need to develop drugs that are more effective, preferential (to neoplastic cells), and accessible remains. This work implements therapeutics that addresses those concerns while demonstrating efficacy within both pediatric and adult cancers. An evaluation of the anticancer potential of nitric oxide (NO) releasing S-nitrosothiol based anticancer therapeutics is presented herein. In the determination of clinical translatability of a drug, it is essential to understand the desired outcome and potential sources of error prior to execution of analyses and the corresponding methodologies and measurements. Thus, an in-depth analysis of indicators for therapeutic efficacy using tumor-derived cell lines and a detailed investigation of the protocol development and potential interferences of three common cellular viability assays is presented prior to the in vitro work detailed in this study. Specifically, this study involves the application of the NO releasing S-Nitrosothiol, S-Nitrosoglutathione (GSNO) in two variations to determine efficacy against pediatric neuroblastomas and adult breast cancers. Initially, two studies explore the application of GSNO in solution to multiple neuroblastoma cell lines of various origins to determine the potential of NO to act as an adjuvant therapeutic in the clinical management of the prevalent pediatric cancer neuroblastoma. These studies highlight the incredible impact of NO on clonogenic capacity as well as remarkable discriminatory characteristics between neoplastic and healthy cells. Further, the insight presented regarding the mechanism of action of NO on neuroblastomas expands the comprehension of NO-based anticancer therapeutics. Excitingly, when the same GSNO preparation is subsequently applied to more common adult breast cancers to determine if therapeutic efficacy is maintained, results display analogous consequences to those mentioned above. The final study in this dissertation will also explore another application of solution-phase GSNO to adult breast malignancies by combining it with a novel SMYD-3 inhibitor, termed Inhibitor-4 (by collaborators). Since Inhibitor-4 has been shown to similarly impact viability, clonogenic capacity, and apoptosis, this combination is expected to reveal a greater impact than each individual treatment. Overall, an analysis of the significance and feasibility of NO-based therapeutics, delivered via GSNO, is explored to determine their potential application in the clinical management of various cancers. Ultimately, this work expands the knowledge of the practicality, mechanism of action, and effectiveness of NO-based anticancer therapeutics in various cancers with a specific focus on its applicability in neuroblastomas, a malignancy where minimal focus has been placed on NO as a treatment option.Item Open Access Development of a nitric oxide measurement method in tissue media(Colorado State University. Libraries, 2012) Bishop, Cherelle M., author; Reynolds, Melissa, advisor; Henry, Charles, committee member; Tobet, Stuart, committee memberNitric oxide (NO) is involved in many biological pathways such as vasodilatation and cellular migration. The biological roles of NO have been most heavily investigated using cell and tissue culture models. The limitations with current analytical measurement methods used most commonly with these studies, however, are that they often do not record in real-time or measure NO directly. This makes it difficult to understand the concentration dependent response activity of NO. To overcome these limitations, a measurement method has been developed that enables the real-time measurement of NO in buffered tissue media (pH 7.4, buffered with CO2 gas, 37 °C). The design of our system included multi-volume custom sample cells with a pH probe and multiple gas supply inputs, a flow regulated CO2 gas system and a chemiluminescence detector. Results demonstrated the expected first-order NO release kinetics using a model NO donor (MAHMA/NO) in phosphate buffered saline (PBS) over a specified volume range. The following half-lives were found: 63±2 s (2 mL), 65±2 s (6 mL), 63±4 s (8 mL) and 67±9 s (10 mL). Using this method at these buffer volumes, an experiment was conducted using 11 mM MAHMA/NO stock used to demonstrate that NO release was linearly proportional with respect to buffer volume with a linear fit of R2 =0.9936. The linearity of NO release allowed NO release measurements of 4.4 x 10-7 M MAHMA/NO concentration in 10 mL PBS achieving NO recovery of 117±2 and MAHMA/NO decomposition half-lives 66±2. The analysis of a 10-7 M MAHMA/NO was not measurable previously using other chemiluminescence methods. Subsequent results in tissue media buffered with 5% CO2 at a controlled rate of 20 mL/min showed statistically similar kinetic rates 68±5 s (2 mL) to that of the PBS, demonstrating the ability to measure NO in real time under tissue conditions. The simultaneous pH measurements confirmed that the pH was constant at 7.4 during the NO release portion of the experiment, an important aspect to maintain accurate kinetics. Using this method for NO release measurement in tissue media, another NO donor, DETA/NO, was used to look at steady-state release for 1.5 h. The total NO release was 0.12±0.02 (nmol) and the NO release rate was 22±3 (fmol/s). This is the first analytical measurement method that enables detection of NO release from NO donors in buffered tissue media method mimicking in vitro condition.Item Open Access Evaluation of nitric oxide releasing polymers for wound healing applications(Colorado State University. Libraries, 2015) Wold, Kathryn A., author; Reynolds, Melissa, advisor; Henry, Charles, committee member; Kipper, Matt, committee member; Popat, Ketul, committee member; Williams, John, committee memberChronic, non-healing wounds afflict millions of Americans and represent a costly burden to the healthcare industry. In addition, the overuse and misuse of antibiotics has triggered the widespread emergence of drug-resistant bacteria, making the treatment of infected wounds more challenging. As a result, improved methods for wound care incorporating antibiotic-alternative bactericidal agents are in high demand. Recent wound care advances have focused on the development of dressings incorporating physical structures and biological components which mimic those encountered in a natural wound environment. Nitric oxide (NO), an endogenously produced molecule upregulated to promote cellular function and bactericidal activity during wound healing, has been harnessed in material systems and studied for wound healing potential. This work describes the characterization, bactericidal activity, cell functionality and processing of two NO-releasing polymer systems, one water-soluble and another water-insoluble. The results of this work demonstrate the capability of these polymeric NO-releasing materials to promote high log reductions of planktonic bacteria. Additionally, polymer dosages that promote cell survival and induce cytotoxicity in eukaryotic cells have been determined and nano-scale polymer fibers that maintain NO release properties have been processed. These results represent qualities beneficial towards the development of enhanced materials for the treatment of chronic infected wounds.Item Open Access Metal organic frameworks as heterogenous nitric oxide catalysts for use in the development of therapeutic polymer materials(Colorado State University. Libraries, 2014) Harding, Jacqueline L., author; Reynolds, Melissa, advisor; Prieto, Amy, committee member; Crans, Debbie, committee member; Bailey, Travis, committee member; Worley, Deanna, committee memberImplantable polymeric medical devices are subject to surface biofouling due to the deposition of microbial agents and the accumulation of proteins at the material interface. Consequently, medical devices which are intended for beneficial functions can become a potentially fatal threat. As a result biofouling resistant materials are vigorously sought through the manipulation of material surface properties and by eluting therapeutics on the material surface. Nitric oxide (NO) is a bioactive agent generated by most nucleated cells in the human body and is known to mediate antimicrobial and antithrombus effects while maintain the capacity to promote the proliferation of healthy tissues. As such, the development of NO releasing biomaterials is known to reduce incidences of surface biofouling. However, current NO releasing materials are limited to short lifetimes of used based on limited capacity of exogenous NO which can be incorporated into the material. In order to circumvent this problem the goal of this research is to develop a biomaterial which generates NO from an endogenously supplied source. Metal organic frameworks (MOFs) were selected for investigation as heterogeneous catalysts for the generation of NO from bioavailable NO donors, S-nitrosothiols (RSNOS). MOFs were evaluated as NO catalysts based on their capacity to react with various RSNO substrates and their maintained structural integrity under reaction conditions. Presented herein is the successful demonstration of a Cu-MOF for the catalytic generation of NO from bioavailable RSNOs donors. However, the limited stability of this proof of principle MOF in aqueous solution prompted the development of a MOF-NO catalyst that is suitable for physiological applications through tuning the organic ligands used in the construction of the framework. Finally a two-fold demonstration of the feasibility towards designing composite MOF based biomaterials is presented as blended materials prepared via commercial manufacturing processes and via surface growth of MOFs on flexible polymeric substrates.Item Open Access Nitric oxide generation from S-nitrosothiols via interactivity with polymer-supported metal-organic frameworks(Colorado State University. Libraries, 2018) Neufeld, Megan J., author; Reynolds, Melissa, advisor; Chen, Eugene, committee member; Finke, Richard, committee member; Kipper, Matthew, committee member; Ravishankara, A. R., committee memberCatheters, 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.Item Open Access Nitric oxide-releasing or generating surfaces for blood-contacting medical devices(Colorado State University. Libraries, 2020) Zang, Yanyi, author; Reynolds, Melissa, advisor; Kipper, Matt, committee member; Li, Yan Vivian, committee member; Zabel, Mark, committee memberMedical device-induced thrombosis is a major complication that impairs the expected performance of blood-contacting medical devices. Traditional anticoagulation therapies are used to reduce thrombus formation; however, systemic anticoagulants such as heparin increase the risk of thrombocytopenia or even bleeding, which are detrimental to patients who already have injuries. To address these issues, surface modification has been widely studied to improve the performance of blood-contacting medical devices, ranging from biopassive surfaces to biomimetic surfaces. To date, such modifications are not sufficient to prevent blood clotting alone. Supplementary anticoagulation remains necessary to maintain clot-free surfaces. Nitric oxide (NO) is a well-known signaling molecule that has antiplatelet properties. Our approach is to use surfaces that can either release NO via NO donors or promote NO production via an NO catalyst. In this work, a NO-releasing polyelectrolyte multilayer coating effectively reduces platelet adhesion, platelet activation and delay blood clotting on titania nanotube array surfaces. In addition, NO-releasing polymeric surfaces mediate blood serum protein deposition in a manner that prevents platelet adhesion and platelet activation. However, the NO donors used in these two coatings are photo- and thermo- sensitive, and the NO release is limited by the amount of NO donor added to the coating. To overcome these shortcomings, a copper-based metal organic framework (MOF) was used to infinitely promote NO production from NO donors in the blood. The copper-based MOF polymer coating was successfully applied to the surfaces of extracorporeal life support catheters and circulation tubing via custom coating systems. These copper-based MOF-coating also exhibited inherent antibacterial properties under both static and dynamic flow conditions.Item Open Access Synthesis, postsynthetic modification, and investigation of metal-organic frameworks for environmental and biological applications(Colorado State University. Libraries, 2018) Rubin, Heather N., author; Reynolds, Melissa, advisor; Chen, Eugene, committee member; Finke, Richard, committee member; Van Orden, Alan, committee member; James, Susan, committee memberMetal-organic frameworks (MOFs) are unique porous coordination polymers having record-high surface areas, and tunability at both the organic linkers and metal ions. As such, MOFs are advantageous for various applications including electronics, gas adsorption, and separations amongst others. Despite the advantages associated with MOFs, there are several key challenges that must be addressed in order to broadly expand the practicality of these materials. Such challenges include synthetic pitfalls, structural instability, selectivity, and inefficient heterogeneous catalysis. For instance, most MOFs are not stable in moisture-rich environments, which leads to structural collapse even in the open atmosphere. This instability poses a serious limitation for useful applications. In addition, the synthesis of MOF-related ligands is underdeveloped, which can lead to costly or inaccessible materials. To overcome these challenges, one goal of this research is to develop a solution to enhance the kinetic stability of MOFs to water and another is to execute an efficient and cost-effective synthetic strategy to generate the MOFs used herein. CuBTC (copper benzene-1,3,5-tricarboxylate), a commercially available MOF that has been well-studied and designated as having great potential for many applications, undergoes rapid degradation in humid atmospheres. Therefore, a novel synthetic approach was developed to efficiently access NH2BTC on gram-scale. Postsynthetic modification to the amine of the MOF powder material enhances the kinetic stability of the MOF to water. A distinct linear relationship between the number of carbons in the modification and observed water contact angle is described for the first time. This facilitates the first report of reliable access to mixed-ligand frameworks with predictable, calculated wettability and tunable kinetic stability to water. This work is also the first report of functionalizing copper MOFs as well as MOFs containing a benzene-1,3,5-tricarboxylate ligand to alter hydrophobic characteristics. That initial work inspired further exploration of CuNH2BTC as an antibacterial surface when synthetically grown on the surface of carboxymethylated cotton. The resultant material is capable of tunable Cu2+ ion release (via postsynthetic modification) and exceeds current industry standards for antibacterial agents, exhibiting a log-3 or greater reduction in bacteria both on the surface and in solution. As the scientific community continues to explore and understand MOFs, the implementation of these materials for various applications is dramatically increasing. As such, the second part of this research was devoted to applying and manipulating MOFs to better understand the interactions of MOFs with small molecules and ions. The photophysical properties of CuNH2BTC were investigated and specific interactions between anions and metal ions with MOFs were identified, encouraging the strategic design of MOFs to detect target-analytes via changing fluorescence emission properties in dimethylformamide (quenching or enhancing emission intensity or changing emission wavelength). This work provides a prerequisite study towards the development of improved next-generation MOF chemosensors. In addition, the open coordination site of thermodynamically stable porphyrin-based MOFs was exploited for simultaneous heavy metal detection and metal ion removal from aqueous solutions. Lastly, to better understand heterogenous catalysis with MOFs in biologically relevant media water, a 1HNMR method with solvent suppression was implemented and allows for kinetic and mechanistic studies of biologically relevant MOF-catalyzed decomposition of GSNO with thermodynamically stable MOF CuBTTri in H2O and eventually in blood. As a whole this research provides valuable insights as to how MOFs may be strategically designed, manipulated, and utilized for sensing, catalysis, and antibacterial applications.Item Open Access Vascular endothelium glycocalyx-mimetic surfaces designed for blood contacting devices(Colorado State University. Libraries, 2021) Vlcek, Jessi, author; Kipper, Matthew, advisor; Reynolds, Melissa, advisor; Popat, Ketul, committee member; Olver, Christine, committee memberEach year millions of blood-contacting devices are used in clinical scenarios, with contact durations designed to range anywhere from hours to years. Current blood-contacting devices can perform their intended purposes well but require the assistance of systemic drugs to inhibit failure via unfavorable interactions between the material's surface and the surrounding biology. The drugs used to inhibit failure of these devices are associated with side effects that can cause increased morbidity of patients because of their systemic administration. Thus, there is a need to design materials that can inhibit thrombus, inflammation, and infection locally at the surface of a device for the device's lifetime. In this work bio-inspired surfaces were engineered to reduce unfavorable blood-material reactions. The success of the designed surfaces was tested by evaluating their cell-material interactions, whole blood interactions, enzymatic stability, and mechanical durability. The inspiration behind these surfaces is the vascular endothelial glycocalyx, which is the luminal side of blood vessels and inhibits blood coagulation during hemostasis. The vascular endothelial glycocalyx is a meshwork of glycosaminoglycans (GAGs), proteoglycans (PGs), and glycoproteins which are predominantly negatively charged that acts as mediator between the blood and the underlying tissue. The surfaces proposed in this work are made to mimic the glycocalyx in its topography and chemistry by adsorbing polyelectrolyte multilayers (PEMs) onto a substrate, and subsequently adsorbing PG mimics on top of the PEMs. There are two different PG mimics used for this project which are: polyelectrolyte complex nanoparticles (PCNs) and proteoglycan mimetic graft copolymers (GC); both of which will present either heparin (HEP) or chondroitin sulfate (CS). Some of the surfaces will also be made to release nitric oxide (NO) from the surfaces through a modified version of chitosan (CHIT). Additionally, further modifications were made to the PEM surfaces to make them more mechanically durable by 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxysuccinimide (NHS) crosslinking of the CHIT and hyaluronan (HA) layers, and the addition of an initial polydopamine (PDA) layer. In the first chapter of this work outlines the current approaches to blood-contacting materials and their limitations, along with the biological components and processes that they will need to interact. The second chapter evaluates PCN and PEM surfaces that do and do not release NO via their cell-material interactions with key cell types in the processes of thrombosis, inflammation, and infection. Chapter three examines the interactions between two different PG-mimics (PC or GCs) and enzymes when suspended in solution or adsorbed onto PEM surfaces. The fourth chapter includes an evaluation of the mechanical durability of PEM and mechanically improved PEM surfaces, and whole blood evaluations of PG, GC, and modified and unmodified PEM surfaces. Taken together, this work produces multiple bioinspired surfaces that have varying degrees of success in their blood compatibility and longevity.