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Physical incorporation of nitric oxide (NO) releasing materials in biomedical grade polymer matrices to fabricate antimicrobial coatings and devices is an economically viable process. However, achieving long-term NO release with a minimum or no leaching of the NO donor from the polymer matrix is still a challenging task. Herein, (

A large fraction of nosocomial infections is associated with medical devices that are deemed life-threatening in immunocompromised patients. Medical device-related infections are a result of bacterial colonization and biofilm formation on the device surface that affects1 million people annually in the US alone. Over the past few years, light-based antimicrobial therapy has made substantial advances in tackling microbial colonization. Taking the advantage of light and antibacterial properties of nitric oxide (NO), for the first time, a robust, biocompatible, anti-infective approach to design a universal disposable catheter disinfection insert (DCDI) that can both prevent bacterial adhesion and disinfect indwelling catheters in situ is reported. The DCDI is engineered using a photo-initiated NO donor molecule, incorporated in polymer tubing that is mounted on a side glow fiber optic connected to an LED light source. Using a smartphone application, the NO release from DCDI is photoactivated via white light resulting in tunable physiological levels of NO for up to 24 h. When challenged with microorganisms S. aureus and E. coli, the NO-releasing DCDI statistically reduced microbial attachment by99% versus the controls with just 4 h of exposure. The DCDI also eradicated ∼97% of pre-colonized bacteria on the CVC catheter model demonstrating the ability to exterminate an established catheter infection. The smart, mobile-operated novel universal antibacterial device can be used to both prevent catheter infections or can be inserted within an infected catheter to eradicate the bacteria without complex surgical interventions. The therapeutic levels of NO generated via illuminating fiber optics can be the next-generation biocompatible solution for catheter-related bloodstream infections.

Bacterial infections are a hurdle to the application of medical devices, and in the United States alone, more than one million infection cases are reported annually from indwelling medical devices. Infections not only affect the function of medical devices but also risk the lives and health of patients. Nitric oxide (NO) has been used as an antibacterial therapy that kills bacteria without causing resistance and provides many therapeutic effects such as anti-inflammation, antithrombosis, and angiogenesis. Silicone oils have been widely utilized in manufacturing consumer goods, healthcare products, and medical products. Specifically, liquid silicone oils are used as a medical lubricant that creates lubricated interfaces between medical devices and the exterior physiological environment to improve the performance of medical devices. Herein, we report the first primary

Therapeutic agents can be linked to nanoparticles to fortify their selectivity and targeted delivery while impeding systemic toxicity and efficacy loss. Titanium dioxide nanoparticles (TiNPs) owe their rise in biomedical sciences to their versatile applicability, although the lack of inherent antibacterial properties limits its application and necessitates the addition of bactericidal agents along with TiNPs. Structural modifications can improve TiNP’s antibacterial impact. The antibacterial efficacy of nitric oxide (NO) against a broad spectrum of bacterial strains is well established. For the first time, S-nitroso-N-acetylpenicillamine (SNAP), an NO donor molecule, was covalently immobilized on TiNPs to form the NO-releasing TiNP–SNAP nanoparticles. The TiNPs were silanized with 3-aminopropyl triethoxysilane, and N-acetyl-d-penicillamine was grafted to them via an amide bond. The nitrosation was carried out by t-butyl nitrite to conjugate the NO-rich SNAP moiety to the surface. The total NO immobilization was measured to be 127.55 ± 4.68 nmol mg(−1) using the gold standard chemiluminescence NO analyzer. The NO payload can be released from the TiNP–SNAP under physiological conditions for up to 20 h. The TiNP–SNAP exhibited a concentration-dependent antimicrobial efficiency. At 5 mg mL(−1), more than 99.99 and 99.70% reduction in viable Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria, respectively, were observed. No significant cytotoxicity was observed against 3T3 mouse fibroblast cells at all the test concentrations determined by the CCK-8 assay. TiNP–SNAP is a promising and versatile nanoparticle that can significantly impact the usage of TiNPs in a wide variety of applications, such as biomaterial coatings, tissue engineering scaffolds, or wound dressings.

The NO-releasing silicone oil (SNAP–Si) was synthesized and infused on a silicone rubber surface, creating a NO-releasing and antimicrobial biointerface that demonstrated its potential to address medical device infection challenges.

As a gasotransmitter, nitric oxide (NO) regulates physiological pathways and demonstrates therapeutic effects such as vascular relaxation, anti-inflammation, antiplatelet, antithrombosis, antibacterial, and antiviral properties. However, gaseous NO has high reactivity and a short half-life, so NO delivery and storage are critical questions to be solved. One way is to develop stable NO donors and the other way is to enhance the delivery and storage of NO donors from biomaterials. Most of the researchers studying NO delivery and applications are using synthetic polymeric materials, and they have demonstrated significant therapeutic effects of these NO-releasing polymeric materials on cardiovascular diseases, respiratory disease, bacterial infections, etc. However, some researchers are exploring saccharide-based materials to fulfill the same tasks as their synthetic counterparts while avoiding the concerns of biocompatibility, biodegradability, and sustainability. Saccharide-based materials are abundant in nature and are biocompatible and biodegradable, with wide applications in bioengineering, drug delivery, and therapeutic disease treatments. Saccharide-based materials have been implemented with various NO donors (like S-nitrosothiols and N-diazeniumdiolates) via both chemical and physical methods to deliver NO. These NO-releasing saccharide-based materials have exhibited controlled and sustained NO release and demonstrated biomedical applications in various diseases (respiratory, Crohn’s, cardiovascular, etc.), skin or wound applications, antimicrobial treatment, bone regeneration, anticoagulation, as well as agricultural and food packaging. This review aims to highlight the studies in methods and progress in developing saccharide-based NO-releasing materials and investigating their potential applications in biomedical, bioengineering, and disease treatment.

Implant-associated infections arising from biofilm development are known to have detrimental effects with compromised quality of life for the patients, implying a progressing issue in healthcare. It has been a struggle for more than 50 years for the biomaterials field to achieve long-term success of medical implants by discouraging bacterial and protein adhesion without adversely affecting the surrounding tissue and cell functions. However, the rate of infections associated with medical devices is continuously escalating because of the intricate nature of bacterial biofilms, antibiotic resistance, and the lack of ability of monofunctional antibacterial materials to prevent the colonization of bacteria on the device surface. For this reason, many current strategies are focused on the development of novel antibacterial surfaces with dual antimicrobial functionality. These surfaces are based on the combination of two components into one system that can eradicate attached bacteria (antibiotics, peptides, nitric oxide, ammonium salts, light

The presence of bacteria and biofilm on medical device surfaces has been linked to serious infections, increased health care costs, and failure of medical devices. Therefore, antimicrobial biointerfaces and medical devices that can thwart microbial attachment and biofilm formation are urgently needed. Both nitric oxide (NO) and chlorhexidine diacetate (CHXD) are possess broad-spectrum antibacterial properties. In the past, individual polymer release systems of CHXD and NO donor S-nitroso-N-acetylpenicillamine (SNAP) incorporated polymer platforms have attracted considerable attention for biomedical/therapeutic applications. However, the combination of the two surfaces has not yet been explored. Herein, the synergy of NO and CHXD was evaluated to create an antimicrobial medical-grade silicone rubber (SR). The 10 wt% SNAP films were fabricated using solvent casting with a topcoat of CHXD (1, 3, and 5 wt%) to generate a dual-active antibacterial interface. Chemiluminescence studies confirmed the NO release from SNAP-CHXD films at physiologically relevant levels (0.5 – 4 × 10(−10) mol min(−1) cm(−2)) for at least 3 weeks and CHXD release for at least 7 d. Further characterization of the films via SEM-EDS confirmed uniform distribution of SNAP and presence of CHXD within the polymer films without substantial morphological changes, as confirmed by contact angle hysteresis. Moreover, the dual-active SNAP-CHXD films were able to significantly reduce E. coli and S. aureus bacteria (> 3-log reduction) compared to controls with no explicit toxicity towards mouse fibroblast cells. The synergy between the two potent antimicrobial agents will help combat bacterial contamination on biointerfaces and enhance the longevity of medical devices.

In the clinical setting, polyvinyl chloride (PVC) accounts for 25% of all polymers used in medical device applications. However, medical devices fabricated with plasticized PVC, such as endotracheal tubes, extracorporeal circuits (ECCs), or intravenous catheters, can lead to thrombosis and infection complications. Mortality associated with hospital associated infections (HAIs) exceed 100,000 deaths each year. One method to overcome these challenges is to develop bioactive polymers with nitric oxide (NO) release. Nitric oxide exhibits many physiological roles including antibacterial, antithrombic, and anti-inflammatory activity. In this study, plasticized Tygon PVC tubing was impregnated with a NO donor molecule

Foreign body response and infection are two universal complications that occur with indwelling medical devices. In response, researchers have developed different antimicrobial and antifouling surface strategies to minimize bacterial colonization and fibrous encapsulation. In this study, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and silicone oil were impregnated into silicone rubber cannulas (SR-SNAP-Si) using a solvent swelling method to improve the antimicrobial properties and decrease the foreign body response. The fabricated SR-SNAP-Si cannulas demonstrated a stable, prolonged NO release, exhibited minimal SNAP leaching, and maintained sliding angles < 15° for 21 days. SR-SNAP-Si cannulas displayed enhanced antimicrobial efficacy against Staphylococcus aureus in a 7-day biofilm bioreactor study, reducing the viability of adhered bacteria by 99.2 ± 0.2% compared to unmodified cannulas while remaining noncytotoxic toward human fibroblast cells. Finally, SR-SNAP-Si cannulas were evaluated for the first time in a 14- and 21-day subcutaneous mouse model, showing significantly enhanced biocompatibility compared to control cannulas by reducing the thickness of fibrous encapsulation by 60.9 ± 6.1 and a 60.8 ± 10.5% reduction in cell density around the implant site after 3 weeks. Thus, this work demonstrates that antifouling, NO-releasing surfaces can improve the lifetime and safety of indwelling medical devices.

Many Type 1 diabetes patients utilize insulin pumps, which rely on a small subcutaneous insulin infusion cannula. However, insulin cannulas still suffer from infection and inflammation, which impacts the wear time of the insulin cannula, reduces the efficiency of insulin infusion, and requires frequent rotation of the insulin infusion site. Infection and inflammation of continuous insulin infusion pump therapy are growing issues and are estimated to cost billions of dollars globally each year. This study aims to develop a potent antibacterial and antifouling insulin cannula with a synergistic effect of bioinspired polymers, integrating antifouling slippery, liquid-infused porous surface technology with an active nitric oxide (NO) releasing polymer. The cannulas were developed by impregnating the NO donor molecule

In the clinical setting, polyvinyl chloride (PVC) accounts for 25% of all polymers used in medical device applications. However, medical devices fabricated with plasticized PVC, such as endotrachea...

Antimicrobial-lock therapy is an economically viable strategy to prevent/reduce the catheter-related bloodstream infections (CRBSI) that are associated with central venous catheters (CVCs). Herein, we report the synthesis and characterization of the S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), a nitric oxide (NO)-releasing molecule, and for the first time its application as a catheter lock solution to combat issues of bacterial infection associated with indwelling catheters. Nitric oxide is an endogenous gasotransmitter that exhibits a wide range of biological properties, including broad-spectrum antimicrobial activity. The storage stability of the SNACET and the NO release behavior of the prepared lock solution were analyzed. SNACET lock solutions with varying concentrations exhibited tuneable NO release at physiological levels for >18 h, as measured using chemiluminescence. The SNACET lock solutions were examined for their efficacy in reducing microbial adhesion after 18 h of exposure to Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria). SNACET lock solutions with 50 and 75 mM concentrations were found to reduce >99% (ca. 3-log) of the adhered S. aureus and E. coli adhesion to the catheter surface after 18 h. The SNACET lock solutions were evaluated in a more challenging in vitro model to evaluate the efficacy against an established microbial infection on catheter surfaces using the same bacteria strains. A >90% reduction in viable bacteria on the catheter surfaces was observed after instilling the 75 mM SNACET lock solution within the lumen of the infected catheter for only 2 h. These findings propound that SNACET lock solution is a promising biocidal agent and demonstrate the initiation of a new platform technology for NO-releasing lock solution therapy for the inhibition and treatment of catheter-related infections.

The current use of implantable and indwelling medical is limited due to potential microbial colonization leading to severe ailments. The aim of this work is to develop bioactive polymers that can be customized based on patient needs and help prevent bacterial infection. Potential benefits of additive manufacturing technology are integrated with the antimicrobial properties of nitric oxide (NO) to develop NO-releasing biocompatible polymer interfaces for addressing bacterial infections. Using filament-based additive manufacturing and polycarbonateurethane-silicone (PCU-Sil) a range of films possessing unique porosities (Disk-60, Disk-40, solid, capped) were fabricated. The films were impregnated with S-nitroso-N-acetyl-penicillamine (SNAP) using a solvent-swelling process. The Disk-60 porous films had the greatest amount of SNAP (19.59 wt%) as measured by UV-vis spectroscopy. Scanning electron microscopy and energy-dispersive X-ray spectroscopy confirmed an even distribution of SNAP throughout the polymer. The films exhibited structure-based tunable NO-release at physiological levels ranging from 7-14 days for solid and porous films, as measured by chemiluminescence. The antibacterial efficacy of the films was studied against Staphylococcus aureus using 24 h in vitro bacterial adhesion assay. The results demonstrated a >99% reduction of viable bacteria on the surface of all the NO-releasing films compared to unmodified PCU-Sil controls. The combination of 3D-printing technology with NO-releasing properties represents a promising technique to develop customized medical devices (such as 3D-scaffolds, catheters, etc.) with distinct NO-release levels that can provide antimicrobial properties and enhanced biocompatibility.

The diagnosis of keratitis is based on visual exam, tissue cytology, and standard microbial culturing to determine the type of the infectious pathogen. To prescribe appropriate therapy, it is important to distinguish between bacterial, fungal, and viral keratitis, as the treatments are quite different. Diagnosis of the causative organism has a substantial prognostic importance. Further, timely knowledge of the nature of the pathogen is also critical to adapt therapy in patients unresponsive to empiric treatment options, which occurs in 10% of all cases. Currently, the identification of the nature of the pathogen that causes keratitis is achieved via microbial culture screening, which is laboratory-based, expensive, and time-consuming. The most frequent pathogens that cause the corneal ulcers are P. aeruginosa and S. aureus. Here, we report a microchip for rapid (

The most recent guidelines have called for a significant shift towards viral load testing for HIV/AIDS management in developing countries; however point-of-care (POC) CD4 testing still remains an important component of disease staging in multiple developing countries. The advancements in micro/nanotechnologies and consumer electronics have paved the way for mobile healthcare technologies, and the development of point-of-care smartphone-based diagnostic assays for a variety of disease detection and treatment monitoring. Here, we report a simple, rapid (30 minutes) smartphone-based microfluidic chip for automated CD4 testing using a small volume (30 μL) of whole blood. The smartphone-based device includes an inexpensive (

Mitochondria are organized as tubular networks in the cell and undergo fission and fusion. Although several of the molecular players involved in mediating mitochondrial dynamics have been identified, the precise cellular cues that initiate mitochondrial fission or fusion remain largely unknown. In fission yeast (Schizosaccharomyces pombe), mitochondria are organized along microtubule bundles. Here, we employed deletions of kinesin-like proteins to perturb microtubule dynamics and used high-resolution and time-lapse fluorescence microscopy, revealing that mitochondrial lengths mimic microtubule lengths. Furthermore, we determined that compared with WT cells, mutant cells with long microtubules exhibit fewer mitochondria, and mutant cells with short microtubules have an increased number of mitochondria because of reduced mitochondrial fission in the former and elevated fission in the latter. Correspondingly, upon onset of closed mitosis in fission yeast, wherein interphase microtubules assemble to form the spindle within the nucleus, we observed increased mitochondrial fission. We found that the consequent rise in the mitochondrial copy number is necessary to reduce partitioning errors during independent segregation of mitochondria between daughter cells. We also discovered that the association of mitochondria with microtubules physically impedes the assembly of the fission protein Dnm1 around mitochondria, resulting in inhibition of mitochondrial fission. Taken together, we demonstrate a mechanism for the regulation of mitochondrial fission that is dictated by the interaction between mitochondria and the microtubule cytoskeleton. © 2019 Mehta et al.

Mitochondria are organized as tubular networks in the cell and undergo fission and fusion. While several of the molecular players involved in mediating mitochondrial dynamics have been identified, the precise cellular cues that initiate fission or fusion remain largely unknown. In fission yeast, mitochondria are organized along microtubule bundles. Here, we employed deletions of kinesin-like proteins to perturb microtubule dynamics, and determined that cells with long microtubules exhibited long, but fewer mitochondria, whereas cells with short microtubules exhibited short, but several mitochondria due to reduced mitochondrial fission in the former and elevated fission in the latter. Correspondingly, upon onset of closed mitosis in fission yeast, wherein interphase microtubules assemble to form the spindle within the nucleus, we measured increased mitochondrial fission. We determined that the consequent rise in the mitochondrial copy number was necessary to reduce partitioning errors while stochastically partitioning mitochondria between daughter cells. We discovered that the association of mitochondria with microtubules physically impeded the assembly of the fission protein Dnm1 around mitochondria, resulting in inhibition of mitochondrial fission. Taken together, we demonstrate a novel mechanism for regulation of mitochondrial fission that is dictated by the interaction between mitochondria and the microtubule cytoskeleton.