Bioinspired superhydrophobic surfaces with silver and nitric oxide-releasing capabilities to prevent device-associated infections and thrombosis.

Bacteria-associated infections and thrombus formation are the two major complications plaguing the application of blood-contacting medical devices. Therefore, functionalized surfaces and drug delivery for passive and active antifouling strategies have been employed. Herein, we report the novel integration of bio-inspired superhydrophobicity with nitric oxide release to obtain a functional polymeric material with anti-thrombogenic and antimicrobial characteristics. The nitric oxide release acts as an antimicrobial agent and platelet inhibitor, while the superhydrophobic components prevent non-specific biofouling. Widely used medical-grade silicone rubber (SR) substrates that are known to be susceptible to biofilm and thrombus formation were dip-coated with fluorinated silicon dioxide (SiO2) and silver (Ag) nanoparticles (NPs) using an adhesive polymer as a binder. Thereafter, the resulting superhydrophobic (SH) SR substrates were impregnated with S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) to obtain a superhydrophobic, Ag-bound, NO-releasing (SH-SiAgNO) surface. The SH-SiAgNO surfaces had the lowest amount of viable adhered E. coli (> 99.9 % reduction), S. aureus (> 99.8 % reduction), and platelets (> 96.1 % reduction) as compared to controls while demonstrating no cytotoxic effects on fibroblast cells. Thus, this innovative approach is the first to combine SNAP with an antifouling SH polymer surface that possesses the immense potential to minimize medical device-associated complications without using conventional systemic anticoagulation and antibiotic treatments.

Varying material thickness of silicone rubber for tunable nitric oxide release.

Silicone rubber (SR), a common medical-grade polymer used in medical devices, has previously been modified for nitric oxide (NO) releasing capabilities. However, the effects of material properties such as film thickness on NO release kinetics are not well explored. In this study, SR is used in the first analysis of how a polymer's thickness affects the storage and uptake of an NO donor and subsequent release properties. Observed NO release trends show that a polymer's thickness results in tunable NO release. These results indicate how crucial a polymer's thickness is to optimize the NO release in an efficient and effective method.

Superhydrophobic and Conductive Foams with Antifouling and Oil-Water Separation Properties.

Hybrid organic-inorganic materials are attracting enormous interest in materials science due to the combination of multiple advantageous properties of both organic and inorganic components. Taking advantage of a simple, scalable, solvent-free hard-sacrificial method, we report the successful fabrication of three-dimensional hybrid porous foams by integrating two types of fillers into a poly(dimethylsiloxane) (PDMS) framework. These fillers consist of hydrophobic electrically conductive graphene (GR) nanoplatelets and hydrophobic bactericidal copper (Cu) microparticles. The fillers were utilized to create the hierarchical rough structure with low-surface-energy properties on the PDMS foam surfaces, leading to remarkable superhydrophobicity/superoleophilicity with contact angles of 158 and 0° for water and oil, respectively. The three-dimensional interconnected porous foam structures facilitated high oil adsorption capacity and excellent reusability as well as highly efficient oil/organic solvent-water separation in turbulent, corrosive, and saline environments. Moreover, the introduction of the fillers led to a significant improvement in the electrical conductivity and biofouling resistance (vs whole blood, fibrinogen, platelet cells, and Escherichia coli) of the foams. We envision that the developed composite strategy will pave a facile, scalable, and effective way for fabricating novel multifunctional hybrid materials with ideal properties that may find potential use in a broad range of biomedical, energy, and environmental applications.

A dual-action nitric oxide-releasing slippery surface for extracorporeal organ support: Dynamic in vitro hemocompatibility evaluation.

Numerous biomaterials have been developed for application in blood-contacting medical devices to prevent thrombosis; however, few materials have been applied to full-scale devices and evaluated for hemocompatibility under clinical blood flow conditions. We applied a dual-action slippery liquid-infused (LI) nitric oxide (NO)-releasing material modification (LINO) to full-scale blood circulation tubing for extracorporeal lung support and evaluated the tubing ex vivo using swine whole blood circulated for 6 h at a clinically relevant flow. LINO tubing was compared to unmodified tubing (CTRL) and isolated LI and NO-releasing modifications (n = 9/group). The primary objective was to evaluate safety and blood compatibility of this approach, prior to progression to in vivo testing of efficacy in animal models. The secondary objective was to evaluate coagulation outcomes relevant to hemocompatibility. No untoward effects of the coating, such as elevated methemoglobin fraction, were observed. Additionally, LINO delayed platelet loss until 6 h versus the reduction in platelet count in CTRL at 3 h. At 6 h, LINO significantly reduced the concentration of platelets in an activated P-selectin expressing state versus CTRL (32 ± 1% decrease, p = .02). Blood clot deposition was significantly reduced on LINO blood pumps (p = .007) and numerically reduced on tubing versus CTRL. Following blood exposure, LINO tubing continued to produce a measurable NO-flux (0.20 ± 0.06 × 10-10  mol cm-2  min-1 ). LINO is a potential solution to reduce circuit-related bleeding and clotting during extracorporeal organ support, pending future extended testing in vivo using full-scale extracorporeal lung support devices.

Remanufacturing of single-use medical devices: a case study on cross-border collaboration between the UK and Nigeria.

This paper aims to evaluate the current state of the remanufacturing of medical devices, considering the differences between developed and developing countries. With reference to various socio-economic factors, the impact of remanufacturing to sustainability was evaluated and from this, single-use medical devices were deemed to be critical in minimising waste within the medical industry. This is even more critical with increasing use of single-use devices in the Coronavirus disease 2019 (COVID 19) pandemic. It was identified that cleaning is a key consideration for ensuring a safe remanufacturing process that would minimise the risk of infection to patients. Therefore, this process was evaluated and appropriate recommendations made. Although there may be some challenges, further research would be required for integration of the methodology and process outlined into the medical sector.

Bio-inspired hemocompatible surface modifications for biomedical applications.

When blood first encounters the artificial surface of a medical device, a complex series of biochemical reactions is triggered, potentially resulting in clinical complications such as embolism/occlusion, inflammation, or device failure. Preventing thrombus formation on the surface of blood-contacting devices is crucial for maintaining device functionality and patient safety. As the number of patients reliant on blood-contacting devices continues to grow, minimizing the risk associated with these devices is vital towards lowering healthcare-associated morbidity and mortality. The current standard clinical practice primarily requires the systemic administration of anticoagulants such as heparin, which can result in serious complications such as post-operative bleeding and heparin-induced thrombocytopenia (HIT). Due to these complications, the administration of antithrombotic agents remains one of the leading causes of clinical drug-related deaths. To reduce the side effects spurred by systemic anticoagulation, researchers have been inspired by the hemocompatibility exhibited by natural phenomena, and thus have begun developing medical-grade surfaces which aim to exhibit total hemocompatibility via biomimicry. This review paper aims to address different bio-inspired surface modifications that increase hemocompatibility, discuss the limitations of each method, and explore the future direction for hemocompatible surface research.

Bioinspired ultra-low fouling coatings on medical devices to prevent device-associated infections and thrombosis.

Addressing thrombosis and biofouling of indwelling medical devices within healthcare institutions is an ongoing problem. In this work, two types of ultra-low fouling surfaces (i.e., superhydrophobic and lubricant-infused slippery surfaces) were fabricated to enhance the biocompatibility of commercial medical grade silicone rubber (SR) tubes that are widely used in clinical care. The superhydrophobic (SH) coatings on the tubing substrates were successfully created by dip-coating in superhydrophobic paints consisting of polydimethylsiloxane (PDMS), perfluorosilane-coated hydrophobic zinc oxide (ZnO) and copper (Cu) nanoparticles (NPs) in tetrahydrofuran (THF). The SH surfaces were converted to lubricant-infused slippery (LIS) surfaces through the infusion of silicone oil. The anti-biofouling properties of the coatings were investigated by adsorption of platelets, whole blood coagulation, and biofilm formation in vitro. The results revealed that the LIS tubes possess superior resistance to clot formation and platelet adhesion than uncoated and SH tubes. In addition, bacterial adhesion was investigated over 7 days in a drip-flow bioreactor, where the SH-ZnO-Cu tube and its slippery counterpart significantly reduced bacterial adhesion and biofilm formation of Escherichia coli relative to control tubes (>5 log10 and >3 log10 reduction, respectively). The coatings also demonstrated good compatibility with fibroblast cells. Therefore, the proposed coatings may find potential applications in high-efficiency on-demand prevention of biofilm and thrombosis formation on medical devices to improve their biocompatibility and reduce the risk of complications from medical devices.

Development of Novel Amphotericin B-Immobilized Nitric Oxide-Releasing Platform for the Prevention of Broad-Spectrum Infections and Thrombosis.

Indwelling medical devices currently used to diagnose, monitor, and treat patients invariably suffer from two common clinical complications: broad-spectrum infections and device-induced thrombosis. Currently, infections are managed through antibiotic or antifungal treatment, but the emergence of antibiotic resistance, the formation of recalcitrant biofilms, and difficulty identifying culprit pathogens have made treatment increasingly challenging. Additionally, systemic anticoagulation has been used to manage device-induced thrombosis, but subsequent life-threatening bleeding events associated with all available therapies necessitates alternative solutions. In this study, a broad-spectrum antimicrobial, antithrombotic surface combining the incorporation of the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) with the immobilization of the antifungal Amphotericin B (AmB) on polydimethylsiloxane (PDMS) was developed in a two-step process. This novel strategy combines the key advantages of NO, a bactericidal agent and platelet inhibitor, with AmB, a potent antifungal agent. We demonstrated that SNAP-AmB surfaces significantly reduced the viability of adhered Staphylococcus aureus (99.0 ± 0.2%), Escherichia coli (89.7 ± 1.0%), and Candida albicans (93.5 ± 4.2%) compared to controls after 24 h of in vitro exposure. Moreover, SNAP-AmB surfaces reduced the number of platelets adhered by 74.6 ± 3.9% compared to controls after 2 h of in vitro porcine plasma exposure. Finally, a cytotoxicity assay validated that the materials did not present any cytotoxic side effects toward human fibroblast cells. This novel approach is the first to combine antifungal surface functionalization with NO-releasing technology, providing a promising step toward reducing the rate of broad-spectrum infection and thrombosis associated with indwelling medical devices.

Characterization of a nitric oxide (NO) donor molecule and cerium oxide nanoparticle (CNP) interactions and their synergistic antimicrobial potential for biomedical applications.

HYPOTHESIS: Broad-spectrum antimicrobials are needed to mitigate the complicated nature of antibiotic-resistant infections. It is imperative to formulate new antimicrobials by combining agents with different mechanisms and broader microbial targets. A combined antimicrobial solution could be a highly critical step towards developing a strategy to prevent polymicrobial infections. Herein, we have investigated the interaction and antimicrobial potential of a solution that contains cerium oxide nanoparticles (CNP) and a nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP). It is hypothesized that these two agents induce synergistic effects and would provide broad antimicrobial effects since CNP is known to be an effective antifungal agent while NO released by SNAP is known to be a potent bactericidal agent. EXPERIMENTS: Different concentrations of SNAP and CNP were combined in a solution and tested for colloidal stability, NO release, mammalian cell cytotoxicity, and antimicrobial efficacy against Staphylococcus aureus, Escherichia coli, and Candida albicans, accounting for Gram-positive bacteria, Gram-negative bacteria, and fungi, respectively. FINDINGS: SNAP and CNP combined in equimolar solution of 3 mM were found to be highly virulent for all microbes tested compared to higher amounts of the treatments required individually. These results hold a promising outlook toward the development of broad-spectrum antimicrobial coatings and films with the potential to prevent polymicrobial infections and further enhance biomedical device usage and applications.

Highly hydrophobic polytetrafluoroethylene particle immobilization via polydopamine anchor layer on nitric oxide releasing polymer for biomedical applications.

Biomedical surface-associated infections and thrombus formation are two major clinical issues that challenge patient safety and patient the fate of a medical device in the body . Single platform multifunctional surfaces are critical to address both these indwelling medical device-related problems. In this work, bio-inspired approaches are employed to fabricate a polymer composite with a versatile surface that can reduce bacterial infections and platelet adhesion in vitro. In the first bio-inspired approach, the functionality of nitric oxide (NO) produced by endothelial cell lining of blood vessels is mimicked through incorporation of S-nitroso-N-acetylpenicillamine (SNAP) within a CarboSil-2080A™ (CarboSil) polymer composite matrix. The second approach involves utilizing mussel adhesive chemistry, via polydopamine (PDA) to immobilize polytetrafluoroethylene (PTFE) particles on the polymer composite surface. The PTFE coating facilitates a decrease in wettability by making the polymer composite surface highly hydrophobic (contact angle ca. 120°). The surface of the fabricated polymer composite , CarboSil SNAP-PTFE, had a cobblestone-like structured appearance as characterized through scanning electron microscopy (SEM). Water contact angle (WCA) and surface tension measurements indicated no significant coating losses after 24 h under physiological conditions. NO surface flux was measured and analyzed for 5 days using a chemiluminescence-based nitric oxide analyzer and was found to be within the physiological range. CarboSil SNAP-PTFE reduced adhered bacteria (99.3 ± 0.5% for Gram-positive S. aureus and 99.1 ± 0.4% for Gram-negative E. coli) in a 24 h in vitro study. SEM analysis showed the absence of biofilm formation on CarboSil SNAP-PTFE polymer composites, while present on CarboSil in 24 h exposure to S. aureus. Platelet adhesion was reduced by 83.3 ± 4.5%. Overall, the results of this study suggest that a combination of NO-releasing CarboSil with PTFE coating can drastically reduce infection and platelet adhesion.

Fabrication of Bacteria- and Blood-Repellent Superhydrophobic Polyurethane Sponge Materials.

Biofilm and thrombus formation on surfaces results in significant morbidity and mortality worldwide, which highlights the importance of the development of efficacious fouling-prevention approaches. In this work, novel highly robust and superhydrophobic coatings with outstanding multiliquid repellency, bactericidal performance, and extremely low bacterial and blood adhesion are fabricated by a simple two-step dip-coating method. The coatings are prepared combining 1H,1H,2H,2H-perfluorooctyltriethoxysilane (FAS-17)-coated hydrophobic zinc oxide and copper nanoparticles to construct hierarchical micro/nanostructures on commercial polyurethane (PU) sponges followed by polydimethylsiloxane (PDMS) treatment that is used to improve the binding degree between the nanoparticles and the sponge surface. The micro/nanotextured samples can repel various liquids including water, milk, coffee, juice, and blood. Relative to the original PU, the superhydrophobic characteristics of the fabricated sponge cause a significant reduction in the adhesion of bacteria (Staphylococcus aureus) by up to 99.9% over a 4-day period in a continuous drip-flow bioreactor. The sponge is also highly resistant to the adhesion of fibrinogen and activated platelets with ∼76 and 64% reduction, respectively, hence reducing the risk of blood coagulation and thrombus formation. More importantly, the sponge can sustain its superhydrophobicity even after being subjected to different types of harsh mechanical damage such as finger-wiping, knife-scratching, tape-peeling, hand-kneading, hand-rubbing, bending, compress-release (1000 cycles) tests, and 1000 cm sandpaper abrasion under 250 g of loading. Hence, this novel hybrid surface with robustness and the ability to resist blood adhesion and bacterial contamination makes it an attractive candidate for use in diverse application areas.

Silk Nanoparticles: A Natural Polymeric Platform for Nitric Oxide Delivery in Biomedical Applications.

In this study, the preparation and characterization of nitric oxide (NO) releasing silk fibroin nanoparticles (SF NPs) are described for the first time. S-Nitroso-N-acetylpenicillamine (SNAP)-loaded SF NPs (SNAP-SF NPs) were prepared via an antisolvent/self-assembling method by adding a SNAP/ethanol solution to an aqueous SF solution and freeze-thawing. The prepared SNAP-SF NPs had a diameter ranging from 300 to 400 nm and an overall negative charge of -28.76 ± 0.73 mV. Among the different SNAP/SF ratios tested, the highest encapsulation efficiency (18.3 ± 1.3%) and loading capacity (9.1 ± 0.6%) values were attributed to the 1:1 ratio. The deconvolution of the amide I band in the FTIR spectra of SF NPs and SNAP-SF NPs showed an increase in the ß-sheet content for SNAP-SF NPs, confirming the hydrophobic interactions between SNAP and silk macromolecules. SNAP-SF NPs released up to 1.31 ± 0.02 × 10-10 mol min-1 mg-1 NO over a 24 h period. Moreover, SNAP-SF NPs showed concentration-dependent antibacterial effects against methicillin-resistant Staphylococcus aureus and Escherichia coli. Furthermore, they did not elicit any marked cytotoxicity against 3T3 mouse fibroblast cells at concentrations equal to or below 2 mg/mL. Overall, these results demonstrated that SNAP-SF NPs have great potential to be used as a NO delivery platform for biomedical applications such as tissue engineering and wound healing, where synergistic properties of SF and NO are desired.

Mimicking the Endothelium: Dual Action Heparinized Nitric Oxide Releasing Surface.

The management of thrombosis and bacterial infection is critical to ensure the functionality of medical devices. While administration of anticoagulants is the current antithrombotic clinical practice, a variety of complications, such as uncontrolled hemorrhages or heparin-induced thrombocytopenia, can occur. Additionally, infection rates remain a costly and deadly complication associated with use of these medical devices. It has been hypothesized that if a synthetic surface could mimic the biochemical mechanisms of the endothelium of blood vessels, thrombosis could be reduced, anticoagulant use could be avoided, and infection could be prevented. Herein, the interfacial biochemical effects of the endothelium were mimicked by altering the surface of medical grade silicone rubber (SR). Surface modification was accomplished via heparin surface immobilization (Hep) and the inclusion of a nitric oxide (NO) donor into the SR polymeric matrix to achieve synergistic effects (Hep-NO-SR). An in vitro bacteria adhesion study revealed that Hep-NO-SR exhibited a 99.46 ± 0.17% reduction in viable bacteria adhesion compared to SR. An in vitro platelet study revealed Hep-NO-SR reduced platelet adhesion by 84.12 ± 6.19% compared to SR, while not generating a cytotoxic response against fibroblast cells. In a 4 h extracorporeal circuit model without systemic anticoagulation, all Hep-NO-SR samples were able to maintain baseline platelet count and device patency; whereas 66% of SR samples clotted within the first 2 h of study. Results indicate that Hep-NO-SR creates a more hemocompatible and antibacterial surface by mimicking two key biochemical functions of the native endothelium.

Versatile biomimetic medical device surface: hydrophobin coated, nitric oxide-releasing polymer for antimicrobial and hemocompatible applications.

In medical device design, there is a vital need for a coating that promotes treatment of the patient and simultaneously prevents fouling by biomacromolecules which in turn can progress to infections, thrombosis, and other device-related complications. In this work, hydrophobin SC3 (SC3), a self-assembling amphiphilic protein, was coated on a nitric oxide (NO) releasing medical grade polymer to provide an antifouling layer to work synergistically with NO's bactericidal and antiplatelet activity (SC3-NO). The contact angle of SC3 samples were ∼30% lesser than uncoated control samples and was maintained for a month in physiological conditions, demonstrating a stable, hydrophilic coating. NO release characteristics were not adversely affected by the SC3 coating and samples with SC3 coating maintained NO release. Fibrinogen adsorption was reduced over tenfold on SC3 coated samples when compared to non-SC3 coated samples. The viable cell count of adhered bacteria (Staphylococcus aureus) on SC3-NO was 79.097 ± 7.529% lesser than control samples and 49.533 ± 18.18% lesser than NO samples. Platelet adherence on SC3-NO was reduced by 73.407 ± 14.59% when compared to control samples and 53.202 ± 25.67 when compared to NO samples. Finally, the cytocompatibility of SC3-NO was tested and proved to be safe and not trigger a cytotoxic response. The overall favorable results from the physical, chemical and biological characterization analyses demonstrate the novelty and importance of a naturally-produced antifouling layer coated on a bactericidal and antiplatelet polymer, and thus will prove to be advantageous in a multitude of medical device applications.

Hemoglobin San Diego: An Uncommon Cause of Hereditary Erythrocytosis Discovered Incidentally in a Military Trainee.

High-affinity hemoglobinopathies are a rare clinical entity that commonly presents as an isolated erythrocytosis in asymptomatic individuals. We report such a case involving an 18-year-old active duty military trainee who presented to the hematology clinic after an isolated erythrocytosis was incidentally discovered during a flight physical. The patient was asymptomatic but did report a family history of erythrocytosis in his mother and maternal grandmother which intermittently required venesection. Initial history and physical exam were unremarkable. P50 RBC Oxygen Dissociation showed a left-shifted oxygen dissociation curve, although hemoglobin electrophoresis did not reveal an abnormal hemoglobin variant. A ß-globin variant was identified via mass spectrometry and sequencing that was consistent with the rare high-oxygen affinity hemoglobin variant designated hemoglobin San Diego. This patient was medically cleared to return to training without limitations and counseled regarding the potential significance of being a carrier of this rare hemoglobin variant. This case represents the first observation of hemoglobin San Diego in the U.S. military population.

Catalyzed Nitric Oxide Release Via Cu Nanoparticles Leads to an Increase in Antimicrobial Effects and Hemocompatibility for Short Term Extracorporeal Circulation.

Devices used for extracorporeal circulation are met with two major medical concerns: thrombosis and infection. A device that allows for anticoagulant-free circulation while reducing risk of infection has yet to be developed. We report the use of a copper nanoparticle (Cu NP) catalyst for the release of nitric oxide (NO) from the endogenous donor S-nitrosoglutathione (GSNO) in a coating applied to commercial Tygon S3™ E-3603 poly(vinyl chloride) tubing in order to reduce adhered bacterial viability and the occurrence thrombosis for the first time in an animal model. Cu GSNO coated material demonstrated a nitric oxide (NO) release flux ranging from an initial flux of 6.3 ± 0.9 ×10-10 mol cm-2 min-1 to 7.1 ± 0.4 ×10-10 mol cm-2 min-1 after 4 h of release, while GSNO loops without Cu NPs only ranged from an initial flux of 1.1 ± 0.2 ×10-10 mol cm-2 min-1 to 2.3 ± 0.2 ×10-10 mol cm-2 min-1 after 4 h of release, indicating that the addition of Cu NPs can increase NO flux up to five times in the same 4 h period. Additionally, a 3-log reduction in S. aureus and 1-log reduction in P. aeruginosa was observed in viable bacterial adhesion over a 24 h period compared to control loops. A Cell Counting Kit-8 (CCK-8) assay was used to validate no overall cytotoxicity towards 3T3 mouse fibroblasts. Finally, extracorporeal circuits were coated and exposed to 4 h of blood flow under an in vivo rabbit model. The Cu GSNO combination was successful in maintaining 89.3% of baseline platelet counts, while the control loops were able to maintain 67.6% of the baseline. These results suggest that the combination of Cu NPs with GSNO increases hemocompatibility and antimicrobial properties of ECC loops without any cytotoxic effects towards mammalian cells.

New agents in renal cell carcinoma.

Prior to 2005, the treatment options for metastatic renal cell carcinoma (mRCC) were limited. There has been a proliferation of agents since the introduction of sorafenib, sunitinib, and becavicumab for clinical use in advanced renal cell carcinoma. Recently, four new agents have been approved by the US Food and Drug Administration (FDA) for use in mRCC. These agents come from two unique targeted pathways for RCC, tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors. This review examines the investigational evolution, phases of development, adverse event profiles, and future directions of pazopanib, axitinib, everolimus, and temsirolimus as well as new novel agents being explored in clinical trials for these targeted pathways.