New Antimicrobial Silver Nanotechnology for Percutaneous Devices in the Cath Lab: Interview With Bruce Gibbins, PhD

Describe the SilvaGard Antimicrobial Surface Treatment. How does it work?

SilvaGard is a surface deposition technology that applies monodispersed silver nanoparticles to the surface of devices. The application involves a dipping process that results in the uniform deposition of the antimicrobial particles over the treated surfaces. The particles bind tightly to the surfaces of nearly all materials. Silver is a potent, broad-spectrum antimicrobial. The SilvaGard applications are an effective method of depositing this potent antimicrobial to the surface without changing any of its functional characteristics other than to impart the prevention of biofilm formation on the device.

When was SilvaGard created? Has this technology been approved or patented? If so, how long has it been in use?

AcryMed, Inc., building on years of research developing silver antimicrobial burn and wound treatments, has produced this new technology. Patents are pending, and the technology has been licensed for its first application involving a percutaneous device that is currently in production. AcryMed, Inc., a pioneer in the advancement of silver antimicrobial burn and wound dressings, was the first company to successfully incorporate ionic silver into advanced moisture-containing wound dressings and the first to market a silver antimicrobial hydrogel. AcryMed markets these products worldwide under the brand name SilvaSorb^®.

Describe some of SilvaGard s benefits.

AcryMed's new silver antimicrobial nanotechnology, SilvaGard, is neither a direct incorporation (into the materials used) nor a coating (on top of the surface of the device). SilvaGard is a wet dip-type treatment that leads to both the formation and deposition of nanoparticle silver to the surfaces of devices. The process can be either aqueous- or solvent-based so that it is compatible with all types of materials. SilvaGard antimicrobial nanoparticle silver provides an effective, broad-spectrum antimicrobial functionalization to the surface of devices. This prevents biofilm formation, which typically serves as the reservoir for pathogens that cause recurrent infections associated with indwelling devices. The silver nanoparticles of approximately 10 nm in diameter are metallic silver, which dissolves slowly in body fluids to serve as a continuous supply of ionic silver until the silver is exhausted. This functional life of the particles is dependent on surface loading of silver. Its efficacy can range from hours to more than 150 days. SilvaGard surface treatment has no effect on the dimensions or other properties of the device, and has been successfully used on silicone, Pebax, PP, PE, nylon latex, stainless steel, titanium, Teflon, and other materials. SilvaGard technology can add from ? 1 µg/cm2 to 32 µg/cm² silver (micrograms per square centimeter) depending on medical application requirements. In the case of advanced medical applications, even greater amounts can be added. A high degree of control enables the process to be masked to treat only the target sites on the device. In some cases, a light amber coloration may be visible on some materials, connoting a silver-treated antimicrobial device.

Why do you think AcryMed chose the ionic form of silver for this product? What are the healing properties of silver? In particular, how is silver able to fight infections?

The process deposits particles of metallic silver, each with very high surface area-to-volume ratio. This aspect allows silver to transition to the ionic state, which will dissolve in the surrounding fluid. The ionic form is the only form of silver that has antimicrobial activity. AcryMed researchers were aware that the ionic form of silver (Ag+) was highly antimicrobial, with the ability to kill a very broad spectrum of medically relevant bacteria (gram+ and gram-), as well as fungi (molds and yeasts). Ionic silver is also oligodynamic, which means that it is antimicrobial at extremely low doses, as low as 0.001 ppm. Although silver is a heavy metal, in these very small amounts, it is nontoxic to human cells, and therefore very safe. As an industry leader in silver antimicrobial technology, it was a natural next step for AcryMed to apply the years of expertise that produced our burn and wound technology, SilvaSorb, to the challenge of preventing hospital-related infections associated with percutaneous and indwelling medical devices. Unlike antibiotics, which are designed to fight a specific microorganism, ionic silver has a mechanism that simultaneously attacks multiple sites (up to 10) in the cell which prevents it from reproducing or kills it. Pathogenic cells cannot mutate fast enough to avoid the attack. As a result, there are no known silver-resistant bacteria among the medically relevant strains. It is this property that has caused doctors, surgeons and wound care specialists to consider silver technology for medical devices to prevent and reduce infections. A microorganism goes through radical changes when it transitions from the free living form to living in a biofilm. It accomplishes this adaptation by activating genes or proteins needed for the formation of biofilm. The expression of these genes makes the organism look entirely different, so much so that it could be confused with an entirely different species from its planktonic form. Such significant change makes it difficult to tailor antibiotic drug therapies to fight infection. Up to 40 percent of the proteins in the bacteria cell walls differ between the original planktonic version of the bacteria, and the biofilm forms as a result of a different gene expression. This constant change makes the bacteria extremely difficult to kill. In recent research, as many as five stages of change have been identified in the profile of biofilm proteins throughout the various stages of development. One of the problems that AcryMed overcame for medical device manufacturers was to prevent microorganisms from attaching to the surface of a medical device. The surface of the metallic silver molecule must come in contact with moisture to enable the chemical reaction to take place that releases antimicrobial ionic silver. The more surface area of the metallic silver that comes in contact with moisture, the more antimicrobial ionic silver that is released. AcryMed researchers solved this problem in an unprecedented way by reducing the size of the silver particles to the realm of nanometers a nanometer is one billionth of a meter to take advantage of a common material property (i.e., given a certain mass, the smaller the particles, the greater the surface area). Therefore, the small nano silver particles present a greater surface area available for the chemical reaction that releases silver ions at the surface of the molecule. AcryMed s new silver nanoparticle technology, SilvaGard, produces unprecedented antimicrobial effectiveness at the medical device surface.

What is the incidence of hospital-related infections today? What types of medical devices are associated with the highest risk of infection?

The Centers for Disease Control (CDC) estimate that hospital-related infections, many of them caused by antibiotic-resistant pathogens, are the fifth leading cause of death in the United States. Especially susceptible to these hospital-related or nosocomial infections are patients treated with indwelling and other percutaneous medical devices. These infections cost as much as $47,000 per patient for diagnosis and treatment. Overall, these infections cost hospitals $4.8 billion annually in extended care and treatment. The CDC estimates that over 2 million people annually in the U.S. become infected as a result of nosocomial infections. The highest rate of infection is associated with urological catheters. Other commonly used at-risk devices include percutaneous (through the skin) catheters, central venous (CV) lines, vascular access devices, peripheral lines, intravenous sites, drug delivery catheters, drains, gastric feeding tubes and tracheotomy tubes. Orthopedic percutaneous devices (pins and stabilizers), as well as implantable devices (screws, joint replacements, valves, stents, surgical mesh, and collagen implants) also present risks.

Describe the dangers of biofilm formation on the surfaces of medical devices.

Medical science has discovered that the infections that threaten patients treated with indwelling medical devices are caused by biofilm formation on the surfaces of the device. Biofilms are formed when fast-mutating versions of free-floating individual or planktonic bacteria attach to an interior surface where they multiply, colonize and form a polysaccharide covering to protect the colonies. Biofilms are very difficult to get rid of and can result in serious blood stream infections, organ failure and death. Some studies indicate that 1,500 times more antibiotic is required to kill a biofilm than is necessary to kill planktonic bacteria. Therefore, the key to preventing biofilms is to prevent the planktonic bacteria from colonizing on the surfaces of medical devices. An effective antimicrobial silver surface treatment is the most effective choice.

How does SilvaGard differ from current antimicrobial treatments for medical devices that use direct incorporation of silver or silver coatings?

Our studies indicate that Silvagard technology offers a simpler, less expensive, but more effective, answer to preventing medical device-related infection. To date, a few manufacturers have tried to incorporate antibiotics, antiseptics and antimicrobials into their products. Most of these have proven beneficial in helping to reduce the rate of secondary infections. However, the problem of infection related to indwelling medical devices persists. Even current commercial antimicrobial silver technologies are less than satisfactory for several reasons. These fall into two broad categories: direct incorporation and coatings. Direct incorporation adds small particles of silver or silver salts directly into the device as it is being formed, and is limited to non-metallic devices. The direct incorporation method is used in plastic materials, which are thermoformed or polymerized into the final device (wound dressings, catheters, tubes, trays). There are several drawbacks to this direct silver incorporation process. Direct incorporation of silver may negatively affect the properties of the device during manufacturing and/or use. These problems can be costly to engineer around. It puts silver throughout the polymer, but only the silver at the surface can be mobilized by moisture the remainder is unavailable. Direct silver incorporation may greatly affect the cost of the device. The second commonly used method involves coating the silver onto the outside surfaces of the device. This can be done by methods such as electroplating a metal implant or plasma or sputter coating onto a plastic device. It can also be done by incorporating silver particles or silver salts into a coating that is ionically coupled or painted onto the outside of the device. The drawback of coatings is that the surface properties of the device are changed. Sometimes this can be a benefit, as it is in a lubricious silver coating added to a urological catheter. In most cases, however, coatings alter surfaces negatively, including increasing dimensional thickness. SilvaGard technology is different. There is no special equipment required to apply it. We can control where the SilvaGard is applied, as well as its concentration and the duration of its efficacy. SilvaGard nanoparticles are formed chemically in a solution. They are uniform in size (2-20 nm), and because of proprietary technology, they do not agglomerate to form large particles, but stay in suspension pending application to other materials. Once the SilvaGard solution is prepared, the device is dipped into the solution. This solution containing SilvaGard nano silver particles can be either aqueous or solvent-based, depending on the needs or characteristics of the device. AcryMed controls the amount of nanoparticle silver actually deposited by adjusting the silver concentration and the temperature of the solution, as well as the dwell time in the solution. While the device is in the SilvaGard solution, the nanoparticles attach to the device. Because of their size, the particles carry a small charge that helps them attach to the surface being treated. The attachment is very uniform over the surface of the device. Once treated, the device is removed and rinsed thoroughly, then dried. This process renders the SilvaGard-treated device antimicrobial. The adhesion is such that this silver treatment cannot be removed by scouring or ultrasonic cleaning. Each nanoparticle would theoretically contain a small number of silver atoms. This process forms a monolayer of Ag₂₀ (silver oxide) on the outside of the nanoparticle. The silver oxide then slowly dissolves in the body fluid it encounters. It dissolves to produce Ag+, an ionic antimicrobial silver, which is then available to attack and kill microbes. The vast number of SilvaGard nanoparticles on the surface of the device provides a very large reservoir and surface area of antimicrobial silver for continuous protection. It is this very large surface area of silver that gives SilvaGard good antimicrobial effectiveness at very low concentrations, very low cytotoxicity and long-lasting, sustained release. At the same time, the relatively low concentration of silver (parts per million) plus the slow dissolution of silver into ionic silver, means that SilvaGard-treated devices are not only effective, safe and nontoxic, they also elute such small amounts of silver that there should be no negative interaction with drugs. Elution studies using radioactive silver have predicted that treatment levels can achieve antimicrobial activity for over a year.

Is SilvaGard clinically proven?

Depending on the application and duration requirements, studies show that depositing from 1 µg/cm² to 32 µg/cm² of silver nanoparticles on medical device surfaces can prevent biofilm formation across a broad spectrum of pathogens, including common pathogens such as Staphylococcus aureus, E coli, Pseudomonas aeruginosa, Enterococcus sp, and Candida albicans, to name a few. Studies show that SilvaGard effectively prevents the formation of biofilms of the five previously mentioned medically relevant microbes on medical device surfaces.

Will SilvaGard interact or interfere with drugs as they are being delivered through a catheter?

In addition to SilvaGard's efficacy and adaptability in application, it is important to note that SilvaGard has been clinically proven to be safe for its intended purpose. The presence of silver in patients is not considered a problem for drug incompatibilities. Where a device treated with SilvaGard is used in close association with drugs, it would be recommended to evaluate whether there is any evidence of drug-device interactions that could pose a problem. These tests are straightforward, and furthermore, are commonly conducted when there is modification or improvement of cleared devices.

Is there anything else you'd like to add?

Since we know that a percutaneous indwelling device can act as a wick that promotes the spread of infection in the body, it is important to note that the SilvaGard technology can add extra preventative protection by coating the lumen as well as the exterior surface of the catheter. We also have the capability of masking parts of the medical device surface for selective application. The SilvaGard treatment has been shown to be effective on a wide variety of materials commonly used for medical devices. Treatment conditions can be varied for duration of use, concentration of silver and type of material. However, nearly any material can be effectively rendered antimicrobial with the use of SilvaGard.

SilvaGard is a trademark, and SilvaSorb is a registered trademark of AcryMed, Inc., Portland, Oregon. The SilvaGard technology is covered by U.S. and international patents pending.