Jae Ho Shin

Anti-Biofilm Efficacy of Nitric Oxide-Releasing Silica Nanoparticles

The ability of nitric oxide (NO)-releasing silica nanoparticles to kill biofilm-based microbial cells is reported. Biofilms of Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans were formed in vitro and exposed to NO-releasing silica nanoparticles. Replicative viability experiments revealed that >or= 99% of cells from each type of biofilm were killed via NO release, with the greatest efficacy (>or= 99.999% killing) against gram-negative P. aeruginosa and E. coli biofilms. Cytotoxicity testing demonstrated that the highest dose of NO-releasing silica nanoparticles inhibited fibroblast proliferation to a lesser extent than clinical concentrations of currently administered antiseptics (e.g., chlorhexidine) with proven wound-healing benefits. This study demonstrates the promise of employing nanoparticles for delivering an antimicrobial agent to microbial biofilms.

Bactericidal efficacy of nitric oxide-releasing silica nanoparticles.

The utility of nitric oxide (NO)-releasing silica nanoparticles as novel antibacterial agents is demonstrated against Pseudomonas aeruginosa. Nitric oxide-releasing nanoparticles were prepared via co-condensation of tetraalkoxysilane with aminoalkoxysilane modified with diazeniumdiolate NO donors, allowing for the storage of large NO payloads. Comparison of the bactericidal efficacy of the NO-releasing nanoparticles to 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), a small molecule NO donor, demonstrated enhanced bactericidal efficacy of nanoparticle-derived NO and reduced cytotoxicity to healthy cells (mammalian fibroblasts). Confocal microscopy revealed that fluorescently labeled NO-releasing nanoparticles associated with the bacterial cells, providing rationale for the enhanced bactericidal efficacy of the nanoparticles. Intracellular NO concentrations were measurable when the NO was delivered from nanoparticles as opposed to PROLI/NO. Collectively, these results demonstrate the advantage of delivering NO via nanoparticles for antimicrobial applications.

Antibacterial Fluorinated Silica Colloid Superhydrophobic Surfaces

A superhydrophobic xerogel coating synthesized from a mixture of nanostructured fluorinated silica colloids, fluoroalkoxysilane, and a backbone silane is reported. The resulting fluorinated surface was characterized using contact angle goniometry, scanning electron microscopy (SEM), and atomic force microscopy (AFM). Quantitative bacterial adhesion studies performed using a parallel plate flow cell demonstrated that the adhesion of Staphylococcus aureus and Pseudomonas aeruginosa was reduced by 2.08 ± 0.25 and 1.76 ± 0.12 log over controls, respectively. This simple superhydrophobic coating synthesis may be applied to any surface, regardless of geometry, and does not require harsh synthesis or processing conditions, making it an ideal candidate as a biopassivation strategy.

Biocompatible materials for continuous glucose monitoring devices.

Diabetes mellitus is a worldwide epidemic characterized by chronic hyperglycemia that results from either a deficiency or tolerance in insulin.1 In the United States, 8.3% of the population currently has diabetes and that number is projected to increase to 1 in 3 adults by 2050 if current trends continue.2 As a consequence, diabetes is the seventh leading cause of death with an annual cost burden of

Electrochemical nitric oxide sensors for physiological measurements

174 billion in the United States, including

Nitric oxide-releasing silica nanoparticle inhibition of ovarian cancer cell growth

116 billion in direct medical expenses.2 Blood glucose levels in diabetics fluctuate significantly throughout the day, resulting in serious complications including heart attacks, strokes, high blood pressure, kidney failure, blindness and limb amputation.1–2 Portable glucose sensors give patients the ability to monitor blood glucose levels, manage insulin levels, and reduce the morbidity and mortality of diabetes mellitus. Traditional glucose monitoring techniques are primarily based on the use of electrochemical amperometric glucose sensors. In 1987, Medisense Inc. launched the first personal glucose testing device consisting of a test strip and reader. Over 40 different commercial pocket-sized monitors have been introduced since then.3 To date, the U.S. Food and Drug Administration (FDA) has approved >25 glucose monitors with the majority employing test strips consisting of either glucose dehydrogenase (GDH) or glucose oxidase (GOx) immobilized on a screen-printed electrode.4 The analysis is based on obtaining a small blood sample (<1 μL) through a finger prick that is subsequently introduced into the test strip via capillary action.3–4 While these monitors have augmented the health outcomes for people with diabetes by improving blood glucose management, such monitoring only provides instantaneous blood glucose concentrations that are unable to warn of hyperglycemic or hypoglycemic events in advance. Additionally, the sample collection (i.e., finger prick) method is inconvenient resulting in poor patient compliance. Analytical methods that enable continuous monitoring of blood glucose have thus been sought.5 Continuous glucose monitoring (CGM) provides real-time information on trends (i.e., whether the glucose levels are increasing or decreasing), magnitude, duration, and frequency of glucose fluctuations during the day.5–6 Ideally, analytically functional continuous glucose monitoring devices could be linked to an insulin delivery pump, creating an artificial pancreas.5–6 In this review, we describe progress in the development of continuous glucose monitoring technologies, specifically focusing on subcutaneous implantable electrochemical glucose sensors, which are widely studied and commercially available. We discuss the challenges associated with the development of biocompatible coatings for electrochemical glucose sensors. Borrowing from the ideas of David Williams, we consider sensor coatings to be “biocompatible” if they optimize the clinical relevance of the sensor, avoid any negative local and systemic effects, and elicit the most appropriate local tissue response adjacent to the implant.7

Improving the biocompatibility of in vivo sensors via nitric oxide release

The important biological roles of nitric oxide (NO) have prompted the development of analytical techniques capable of sensitive and selective detection of NO. Electrochemical sensing, more than any other NO detection method, embodies the parameters necessary for quantifying NO in challenging physiological environments such as blood and the brain. In this tutorial review, we provide a broad overview of the field of electrochemical NO sensors, including design, fabrication, and analytical performance characteristics. Both electrochemical sensors and biological applications are detailed.

Superhydrophobic nitric oxide-releasing xerogels

Although the potent antitumor activity of nitric oxide (NO) supports its promise as an antineoplastic agent, effective and selective delivery and action on tumor and not normal cells remains a limiting factor. Nanoparticle-based delivery of NO has been considered as one approach to overcome these limitations. Therefore, we determined the utility of NO delivery using silica nanoparticles and evaluated their antitumor efficacy against human ovarian tumor and nontumor cells. The NO-releasing nanoparticles exhibited enhanced growth inhibition of ovarian tumor cells when compared to both control nanoparticles and a previously reported small molecule NO donor, PYRRO/NO. In addition, the NO-releasing nanoparticles showed greater inhibition of the anchorage-independent growth of tumor-derived and Ras-transformed ovarian cells. Confocal microscopy analysis revealed that fluorescently labeled NO-releasing nanoparticles entered the cytosol of the cell and localized to late endosomes and lysosomes. Furthermore, we observed a nanoparticle size dependency on efficacy against normal versus transformed ovarian cells. Our study provides the first application of nanoparticle-derived NO as an antitumor therapy and merits future studies examining nanoparticle formulation for in vivo applications.

Inorganic/Organic Hybrid Silica Nanoparticles as a Nitric Oxide Delivery Scaffold

The continuous, real-time monitoring of clinically important analytes (e.g., PO2, PCO2, pH, K+, Na+, glucose, and lactate) is of great importance to human health care. Despite considerable efforts spanning several decades, the use of in vivo sensors clinically remains limited due to inadequate biocompatibility. The discovery of nitric oxide (NO) as an effective inhibitor of platelet and bacterial adhesion has opened a new direction of research related to designing the next generation of in vivo sensors. In this Highlight article, recent progress in designing more biocompatible in vivo sensors is described, with a particular focus on preparing interfaces that resist biofouling via controlled NO release.

Fluorinated Xerogel-Derived Microelectrodes for Amperometric Nitric Oxide Sensing

Superhydrophobic nitric oxide (NO)-releasing xerogels were prepared by spray-coating a fluorinated silane/silica composite onto N-diazeniumdiolate NO donor-modified xerogels. The thickness of the superhydrophobic layer was used to extend NO release durations from 59 to 105h. The resulting xerogels were stable, maintaining superhydrophobicity for up to 1month (the longest duration tested) when immersed in solution, with no leaching of silica or undesirable fragmentation detected. The combination of superhydrophobicity and NO release reduced viable Pseudomonas aeruginosa adhesion by >2-logs. The killing effect of NO was demonstrated at longer bacterial contact times, with superhydrophobic NO-releasing xerogels resulting in 3.8-log reductions in adhered viable bacteria vs. controls. With no observed toxicity to L929 murine fibroblasts, NO-releasing superhydrophobic membranes may be valuable antibacterial coatings for implants as they both reduce adhesion and kill bacteria that do adhere.