Silver has long been used for its antimicrobial properties. However, the delivery systems available, often in the form of a salt, have been the limiting factor to successful biological use of this noble metal. Nanotechnology and the ability to deliver silver from a nanocrystalline structure has and will markedly improve the biologic value of silver. These advances in crystal chemistry will likely have a dramatic impact on the microbiology, as well as biology of wound healing and control of inflammation. This review will attempt to describe the past, present and future uses of silver in biologic systems focusing on its biological properties on “wounds”.
BIOLOGIC PROPERTIES OF NANOCRYSTALLINE SILVER COMPARED TO OTHER SILVER PRODUCTS
a) Antimicrobial Properties: The aqueous concentration of silver ions released from the nanocrystalline film is approximately 3% of that released from a 0.5% silver nitrate or a 1% silver sulfadiazine cream. However, the biological properties of the silver released from nanocrystals are much greater. Silver resistance has been reported in the literature and is mediated through one of two pathways. Either the silver is tied up in the cell wall and membranes, or it is actively transported out of the cell. Bacterial organisms that have either one of these resistance mechanisms, which are effective up to 1000 µg/mL Ag+, have been tested against the nanocrystalline silver coated dressing. These tests showed that these organisms were susceptible to the silver produced by the nanocrystals, but not to Ag+ from silver nitrate. These findings, as will be described, strongly suggest that other species of silver besides Ag+ are released from the nanocrystals.
a) Antimicrobial Properties: The aqueous concentration of silver ions released from the nanocrystalline film is approximately 3% of that released from a 0.5% silver nitrate or a 1% silver sulfadiazine cream. However, the biological properties of the silver released from nanocrystals are much greater. Silver resistance has been reported in the literature and is mediated through one of two pathways. Either the silver is tied up in the cell wall and membranes, or it is actively transported out of the cell. Bacterial organisms that have either one of these resistance mechanisms, which are effective up to 1000 µg/mL Ag+, have been tested against the nanocrystalline silver coated dressing. These tests showed that these organisms were susceptible to the silver produced by the nanocrystals, but not to Ag+ from silver nitrate. These findings, as will be described, strongly suggest that other species of silver besides Ag+ are released from the nanocrystals.
The lower amount Ag+ released should also decrease the potential of silver toxicity to cells, if it exists, by a substantial margin when compared to the other silver agents. The nanocrystal coating contains 0.84-1.34 mg silver/cm2 of dressing, is resistant to abrasion, does not adhere to the wound and is flexible. In another study nanocrystalline silver was extracted from the silver delivery system Acticoat by incubating the dressing in nanopure water at 37°C in a shaking incubator, and silver concentrations were measured using atomic absorption spectrophotometry. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined using five bacterial isolates of clinical interest, and results were compared for nanocrystal silver, silver nitrate and silver sulfadiazine, based upon total silver. Nanocrystalline silver had similar MIC and MBC values when compared to three silver containing agents. Kill kinetics were also studied, using 2.0 cm x 2.0 cm pieces of silver dressing, and the same sized pieced of dressing impregnated with either silver nitrate (100µl of 1% solution. This results in a final concentration of 0.5% silver nitrate) or silver sulfadiazine (370mg of a 1% cream). Bacterial survival was measured using a plate counting technique. Nanocrystal silver demonstrated the fastest kill times for the five bacteria used. In most instances with Nanocrystal silver, bacterial survival was undetectable 30 minutes after inoculation, whereas at least 2-4 hours elapsed before no viable cells were detected with silver nitrate or silver sulfadiazine. These findings strongly suggest that silver species in addition to Ag+, are released from the nanocrystalline film which are responsible for the more potent antimicrobial properties. To date the nanocrystalline silver system kills all microbes found in a wound including fungi and all current antibiotic resistant strains such as vancomycin resistant enterococcus (VRE) and methicillin resistant Staphylococcus aureus (MRSA).
b) Pro-healing Properties: Although silver in an electro colloidal form, had been reported to improve the healing of indolent wounds in the early 20th century, that finding disappeared with the use of silver salts and complexes. Recently there have been several reported studies of improved re-epithelialization rates across partial thickness wounds with silver in the nanocrystalline form. The mechanism, although unknown at present, does not appear to be due to silver’s antimicrobial action.
c) Anti-inflammatory Properties: Increased wound inflammation not only accentuates pain but markedly impairs healing. Several heavy metals have been reported to decrease surface inflammation, the most recognized being gold. Wound surface inflammation has been reported to be decreased with the use of nanocrystalline silver. Excess metalloproteinases (MMP) are known to increase inflammation by both increasing inflammatory cell exudates and also leading to a non-healing chronic wound. A characteristic of this type of wound is excess surface MMP activity, decreased inhibitory MMP activity and degradation of growth factors by the MMP’s. Nanocrystalline silver has been shown both in vitro and in vivo to decrease but not prevent MMP activity as some activity is needed to remove devitalized tissue. The mechanism for this action also remains unknown. Decreasing the necessary zinc activity required for MMP’s, is one possibility. The other is an effect on the expression or release of pro-inflammatory cytokines.
SUMMARY
The application of nano-technology to develop nanocrystalline silver has led to a highly effective topical antimicrobial agent due not only to a more rapid release of silver cation onto a wound surface, compared to other available silver antimicrobial agents, but likely the release of other silver species as well. In addition, nanocrystalline silver appears to have overall positive biological effects on wound inflammation, healing and likely on a host of as yet undetermined reactions. Current available data only scratches the surface of the potential theoretical benefits of nanocrystalline silver.
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