Silver and Silver Nanoparticles
Jean-Yves Maillard
Philippe Hartemann
KEYWORDS: silver, nanoparticles, mechanisms, efficacy, toxicity, resistance
Silver has been the most used metallic salt for its antimicrobial properties over centuries.1,2,3 There are different forms of silver that can be incorporated in products, including metallic silver (Ag0), silver ions (most common Ag1+, Ag2+, or Ag3+), and silver nanoparticles (nanosilver; AgNPs) for this chapter, ionic silver will be abbreviated to Ag. An AgNP is defined as particulate matter, aggregate, or agglomerate for which 50% or more of the particles in the number size distribution are in the range 1 to 100 nm. The AgNPs can be used in a wide range of matrices and formulations including composites, colloids, fibers, gels, coatings, membranes, and thin films.4,5,6,7,8 The form of silver and concentration, formulations, and matrices can impact antimicrobial efficacy and overall toxicity. The Ag and AgNPs are widely used today for their antimicrobial properties in a wide range of applications including consumer home products, health care industry, clothing and fabric industry, food industry, and construction industry (Table 25.1).8,9,10,11,12,13,14,15,16 The number of clothing items (eg, cleaning textiles, sportswear, gloves, socks, underwear, helmet lining) incorporating Ag/AgNPs as an antimicrobial, notably to control malodors,16,17,18 has rapidly increased in recent years. There are now thousands of products containing silver (AgNPs) for the consumer home and other markets. The AgNPs might be the most commonly used nanomaterials in consumer products (eg, see https://www.nanotech project.org). It is clear from these diverse applications that the majority of Ag- and AgNP-containing products are used in a dry condition as opposed to immersion in liquids (see Table 25.1). This is an important consideration, which will be discussed later. The use of AgNPs in the food industry can be categorized in different stages of food production such as crop harvest (use of Ag/AgNPsbased agricultural disinfectants), food processing (food preparation equipment), and storage (sprays, refrigerators, storage containers).19 In the European Union, no nanomaterials are admitted for use in plastics that come into contact with food unless authorized. The regulation of silver nanoparticles in products is complex and depends on the application.3 In the United States, in contrast, the use of AgNPs in food containers is possible but has to be registered.20 The US Food and Drug Administration (FDA) has issued guidance on the regulation of nanomaterials (https://www.fda.gov/scienceresearch/specialtopics/nano technology/ucm301114.htm). An important use of Ag/AgNPs is in the construction industry notably in paint products, sealants, etc, and incorporated onto various plastics. The AgNPs are also used for disinfection of drinking water, cooling towers, and recreational water applications.2,21
The Ag and AgNPs used for biomedical applications have recently been reviewed.11 Applications include wound dressings, bandages,1,8,12,22,23,24 medical devices such as catheters,25,26,27,28,29,30 bone scaffolds,31,32 and potentially ocular devices.33 The combination of low concentrations of silver ion with hydrogen peroxide (5%) in an aerosol (dry mist) is also used for the disinfection of wards, medical equipments, and ambulances.34,35
The incorporation Ag/AgNPs in medical dressings was introduced in the 20th century with silver foil dressing9,36,37 and then with silver nitrate (0.5%) in compresses for the treatment of burn wounds and particularly for the control of Pseudomonas aeruginosa.38 The development of bacterial resistance to silver nitrate forced a change in formulations with combining actives, notably Ag-sulfonamide (silver sulfadiazine).39,40,41 A number of additional combinations have been used such as silver sulfadiazine with chlorhexidine,42 silver sulfadiazine, and cerium nitrate (Flammacerium).43,44 The combination of Ag or AgNPs with other antimicrobials and various polymers in a dressing aims to improve antimicrobial efficacy with the effective release of Ag/AgNPs, decrease
overall toxicity, and overall improve wound healing.45,46,47,48,49,50,51 The use of antimicrobial (including Ag/AgNPs) dressing is recommended for infected acute and chronic wounds (eg, burns, traumatic wounds, and diabetic ulcers)2 to reduce microbial bioburden that can prevent healing and for the prevention of infection and reinfection. A number of Ag/AgNP-based wound dressings have been authorized on the US market by the FDA.7
overall toxicity, and overall improve wound healing.45,46,47,48,49,50,51 The use of antimicrobial (including Ag/AgNPs) dressing is recommended for infected acute and chronic wounds (eg, burns, traumatic wounds, and diabetic ulcers)2 to reduce microbial bioburden that can prevent healing and for the prevention of infection and reinfection. A number of Ag/AgNP-based wound dressings have been authorized on the US market by the FDA.7
TABLE 25.1 Examples of some Ag and AgNPs applications | ||||||||||||||||
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In dentistry, Ag has been used in amalgams52,53 but is now replaced with more modern materials. Clinical evidence, in vitro and in vivo, originally indicated that Ag can prevent and stop caries in the primary and permanent dentition, although its use can be associated with tooth discoloration and pulp irritation.53 Incorporation of AgNPs in dental materials (polymeric filling materials, cements, denture base materials, artificial teeth, etc) enhances the antimicrobial activity of the material, whereas staining can be reduced with reduced AgNP size for dental and other applications.54,55,56,57,58,59,60,61,62,63,64
The extent of Ag/AgNPs use in so many applications has highlighted it as an effective antimicrobial.65
ANTIMICROBIAL EFFICACYIonic silver and AgNPs have been shown to have broad spectrum of activity.4,6,66,67,68,69,70,71,72,73 Gram-negative bacteria are generally more susceptible to Ag than gram-positive bacteria.74,75 The activity of silver resides in ionic silver at a concentration of 10-9 to 10-6 mol/L while Ag0 is inactive. Exopolysaccharide might reduce the concentration or penetration of ionic silver76 and as such Ag activity against microbial biofilm may be limited. The AgNPs overall has been shown to have a better bactericidal efficacy (ng/L concentrations) than ionic silver (µg/L concentrations).4,66,68,69,70,71,72,73,74,75,76,77,78,79 The AgNPs have also been reported to have some activity in the presence of bacterial biofilms.78,79,80,81 The antimicrobial efficacy of Ag and AgNPs depends on their bioavailability.82 Bioavailability can be reduced by complexation, sorption, and precipitation, for example, in the presence of chloride, sulfide and phosphate, and generally organic matter.83 For this reason, the use of Ag in wounds has limitation both in terms of penetration and reduced bioavailability because of organic matter. The maximum
concentration of available ionic silver attainable in wounds has been estimated not to exceed 1 µg/mL.46 Likewise, activity of AgNPs against biofilm is hampered probably because of aggregation and retarded biosorption.84
concentration of available ionic silver attainable in wounds has been estimated not to exceed 1 µg/mL.46 Likewise, activity of AgNPs against biofilm is hampered probably because of aggregation and retarded biosorption.84
An Ag/AgNPs needs to be in contact with the targeted microorganisms to exert an antimicrobial effect.85 The level of hydration will significantly impact Ag efficacy. In dressings, the release of ionic silver is linked to the level of hydration.86 For dry-surface applications, such as in many consumer products (see Table 25.1), the absence of hydration/moisture would prevent the release of ionic silver and its bioavailability. This unfortunately is not reflected in efficacy test protocols. The most common and accepted antimicrobial surface test is ISO 22196,87 which is based on immersing the test surface in a bacterial test suspension for 24 hours. Such a test condition (100% humidity) maximizes the release and diffusion of ionic silver or other antimicrobial ionic metals or actives and ultimately antimicrobial activity. This test has been criticized for its lack of in situ correlation with surfaces that are not immersed in liquid and kept at a temperature of 37°C.88,89 Further evidence of the lack of AgNPs diffusion from surfaces is given in studies on food packaging. The use of AgNPs in food packaging is considered to be safe15 because AgNPs are not released to the food.90,91 Williams et al92 showed some release of AgNPs from food packaging under high moisture conditions (agar diffusion) or acidic conditions, although the AgNPs released had limited antimicrobial effect only delaying the growth of Salmonella ser Typhimurium. Other efficacy tests include diffusion of Ag/AgNPs either from a disk or material placed on a seeded agar plate or direct diffusion from a well in a seeded agar plate.17,93 These inaccurate and limited methods rely on the diffusion of the antimicrobial active in a moist environment. These methods indicate that Ag/AgNPs/reactive oxygen species (ROS) can diffuse in the agar and inhibit the growth of the target microorganisms, but they do not provide information on the microbicidal activity of Ag/AgNPs products and importantly may not provide any valuable information on the efficacy of Ag/AgNPs in a dry environment.
The concentration exponent of silver nitrate is 1 and as such Ag efficacy will be retained on small dilutions.94 Temperature and pH have little effect on Ag, although an increase in pH will increase efficacy.46 Water hardness will affect Ag efficacy for the reasons described earlier, although the impact on efficacy against gram-positive and gram-negative bacteria might be different.95 The AgNPs efficacy will be affected by size and morphology.27,66,72,96,97 The reported superior efficacy of AgNPs over Ag is partially due to an increased surface area of the particle enhancing contact with target microorganisms. In addition, AgNPs might have the ability to generate more ionic silver,1,98 although it is believed that the size, shape, surface coating, and surface charge of the nanoparticles will affect the rate, location, and/or timing of ionic silver release.73,99 Pal et al96 showed that truncated triangular nanoplates, with a high number of {111} facets, were highly reactive compared to other shapes.
To increase antimicrobial efficacy of Ag or AgNPs, combinations with other actives and/or polymers have been used.61,62,82,100 In dressings, ionic silver has been combined with antibiotics (eg, sulfonamide, silver sulfadiazine), chlorhexidine (SilvazineTM), and cerium nitrate (Flammacerium). The type and nature of polymers used in combination of Ag/AgNPs will impact on the amount and release rate of ionic silver.78,101 In the textile industry, the type of material fiber used impacts the release of ionic silver.17
MECHANISMS OF ACTIONIonic silver and AgNPs like many biocides have a multiple target sites in microorganisms. Although their interactions have been primarily studied against bacteria,11,85,102,103 information against viruses104,105 and fungi106,107 has emerged. An AgNPs antimicrobial effect is believed to result from a combination to, or alteration of, microbial proteins, leading eventually to metabolic disruption and structural damage.45,85,102 Some studies have mentioned membrane lipids has a potential target site for Ag action.66,108,109,110 The interaction of Ag against bacterial cells is probably more pronounced at the cytoplasmic membrane, where Ag has been shown not only to inhibit the proton motive force and not surprisingly the respiratory electron transport chain but also to alter membrane permeability resulting in cell death.67,85,102,111,112 The generation of damaging ROS by the bacterial cells following exposure to AgNPs has also been reported.112,113,114,115,116,117,118,119 It has been reported that ROS can be generated not only at the cytoplasmic membrane but also within the bacterial cytoplasm following penetration of Ag/AgNPs.85,120,121 The combination of Ag/AgNPs with hydrogen peroxide or povidone-iodine has been shown result in the production of free radicals causing damage to cytoplasmic membrane and cytoplasm constituents.100,114,122
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