More than 75% of hospital-acquired or nosocomial urinary tract infections are initiated by urinary catheters, which are used during the treatment of 15–25% of hospitalized patients. Among other purposes, urinary catheters are primarily used for draining urine after surgeries and for urinary incontinence. During catheter-associated urinary tract infections, bacteria travel up to the bladder and cause infection. A major cause of catheter-associated urinary tract infection is attributed to the use of non-ideal materials in the fabrication of urinary catheters. Such materials allow for the colonization of microorganisms, leading to bacteriuria and infection, depending on the severity of symptoms. The ideal urinary catheter is made out of materials that are biocompatible, antimicrobial, and antifouling. Although an abundance of research has been conducted over the last forty-five years on the subject, the ideal biomaterial, especially for long-term catheterization of more than a month, has yet to be developed. The aim of this review is to highlight the recent advances (over the past 10 years) in developing antimicrobial materials for urinary catheters and to outline future requirements and prospects that guide catheter materials selection and design.

Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5~4×10−10 mol cm−2 min−1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, five biomedical grade polymers doped with S-nitroso-N-acetylpenicillamine (SNAP) were investigated for their potential to control the release of NO from the SNAP within the polymers, and further control the release of SNAP itself. SNAP in the Elast-eon E2As polymer creates an inexpensive, homogeneous coating that can locally deliver NO (via thermal and photochemical reactions) as well slowly release SNAP. Furthermore, SNAP is surprisingly stable in the E2As polymer, retaining 82% of the initial SNAP after 2 months storage at 37°C. The E2As polymer containing SNAP was coated on the walls of extracorporeal circuits (ECC) and exposed to 4 h blood flow in a rabbit model of extracorporeal circulation to examine the effects on platelet count, platelet function, clot area, and fibrinogen adsorption. After 4 h, platelet count was preserved at 100±7% of baseline for the SNAP/E2As coated loops, compared to 60±6% for E2As control circuits (n=4). The SNAP/E2As coating also reduced the thrombus area when compared to the control (2.3±0.6 and 3.4±1.1 pixels/cm2, respectively). The results suggest that the new SNAP/E2As coating has potential to improve the thromboresistance of intravascular catheters, grafts, and other blood contacting medical devices, and exhibits excellent storage stability compared to previously reported NO release polymeric materials.

Nitric oxide (NO) has been shown to reduce thrombogenicity by decreasing platelet and monocyte activation by the surface glycoprotein, P-selectin and the integrin, CD11b, respectively. In order to prevent platelet and monocyte activation with exposure to an extracorporeal circulation (ECC), a nitric oxide releasing (NORel) polymeric coating composed of plasticized polyvinyl chloride (PVC) blended with a lipophilic N-diazeniumdiolate was evaluated in a 4 hour rabbit thrombogenicity model using flow cytometry. The NORel polymer significantly reduced ECC thrombus formation compared to polymer control after 4 hours blood exposure (2.8 ± 0.7 NORel vs 6.7 ± 0.4 pixels/cm2 control). Platelet count (3.4 ± 0.3 NORel vs 2.3 ± 0.3 × 108/ml control) and function as measured by aggregometry (71 ± 3 NORel vs 17 ± 6 % control) were preserved after 4 hours exposure in NORel versus control ECC. Plasma fibrinogen levels significantly decreased in both NORel and control groups. Platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry was attenuated after 4 hours on ECC to ex vivo collagen stimulation (27 ± 1 NORel vs 40 ± 2 MFI control). Monocyte CD11b expression was reduced after 4 hours on ECC with NORel polymer (87 ± 14 NORel vs 162 ± 30 MFI control). These results suggest that the NORel polymer coatings attenuate the increase in both platelet P-selectin and monocytic CD11b integrin expression in blood exposure to ECCs. These NO-mediated platelet and monocytic changes were shown to improve thromboresistance of these NORel-polymer-coated ECCs for biomedical devices.

The quest for novel therapies to prevent bacterial infections and blood clots (thrombosis) is of utmost importance in biomedical research due to the exponential growth in the cases of thrombosis and blood infections and the emergence of multi-drug-resistant strains of bacteria. Endogenous nitric oxide (NO) is a cellular signaling molecule that plays a pivotal role in host immunity against pathogens, prevention of clotting, and regulation of systemic blood pressure, among several other biological functions. The physiological effect of NO is dose dependent, which necessitates the study of its tunable release kinetics, which is the objective of this study. In the present study, polymer composites were fabricated by incorporating S-nitroso-N-acetylpenicillamine (SNAP) in a medical-grade polymer, Carbosil, and top-coated with varying concentrations of catalytic copper nanoparticles (Cu-NPs). The addition of the Cu-NPs increased the NO release, as well as the overall antimicrobial activity via the oligodynamic effect of Cu. SNAP (10 wt %) composites without Cu-NP coatings showed a NO flux of 1.32 ± 0.6 × 10 mol min cm, whereas Cu-NP-incorporated SNAP films exhibited fluxes of 4.48 ± 0.5 × 10, 4.84 ± 0.3 × 10, and 11.7 ± 3.6 × 10 mol min cm with 1, 3, and 5 wt % Cu-NPs, respectively. This resulted in a significant reduction (up to 99.8%) in both gram-positive and gram-negative bacteria, with very low platelet adhesion (up to 92% lower) as compared to that of the corresponding controls. Copper leachates from the SNAP films were detected using the inductively coupled plasma-mass spectrometry technique and were found to be significantly lower in concentration than the recommended safety limit by the FDA. The cell viability test performed on mouse fibroblast 3T3 cells provided supportive evidence for the biocompatibility of the material in vitro.

Recent reports on liquid-infused materials have shown promise in creating ultra-low fouling surfaces, but are limited in their ability to prevent bacterial proliferation and prevent platelet activation in blood-contacting applications. In this work, a liquid-infused nitric oxide-releasing (LINORel) material is created by incorporating the nitric oxide (NO) donor S-nitroso-acetylpenicillamine (SNAP) and silicone oil in commercial medical grade silicone rubber tubing through a solvent swelling process. This combination provides several key advantages over previous NO-releasing materials, including decreased leaching of NO donor, controlled release of NO, and maintenance of ultra-low fouling property of liquid-infused materials. The LINORel tubing reduces protein adhesion as observed using fluorescence imaging, and platelet adhesion (81.7 ± 2.5%) in vitro over a 2 h period. The LINORel combination greatly reduces bacterial adhesion and biofilm formation of two most common pathogens responsible for hospital acquired infections: gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa (99.3 ± 1.9% and 88.5 ± 3.3% respectively) over a 7-day period in a CDC bioreactor environment. Overall, the LINORel approach provides a synergistic combination of active and passive non-fouling approaches to increase biocompatibility and reduce infection associated with medical devices.