1. Safety

Silver itself is considered to be non-toxic to human cells in vivo.  The only reported complication is the cosmetic abnormality argyria caused by precipitation of silver salts in the skin and leading to a blue-gray color.  Although not yet defined there remains some concerns about the potential of high tissue levels of silver altering enzyme function.  Silver nitrate in vitro has been shown to have a negative impact on fibroblasts, hepatocytes and lymphocytes, but studies on anodically generated silver ions show no impact on mammalian cells in culture.  Clinical evaluations carried out by Bador and Coombs et al. found no tissue toxicity.  The major complications attributed to silver compounds are due to the complex or anion namely the nitrate and sulfadiazine not the silver itself.  Both nitrate and sulfadiazine have been shown to impair fibroblast and epithelial cell proliferation impairing healing allergic reactions to topical silver are rare.

2. Antimicrobial Effects of Silver

Silver exerts its antimicrobial effects by interfering with the respiratory chain at the cytochromes (3).  Silver ions also interfere with components of the microbial electron transport system, bind DNA and inhibit DNA replication.

Silver is effective against a broad range of aerobic, anaerobic, Gram-negative and Gram-positive bacteria, yeast, filamentous fungi and viruses.

In order for silver to be biologically active, it must be in a soluble form such as Ag+ or Ag⁰ clusters.  Ag+ is the only form present in silver nitrate, silver sulfadiazine and other ionic silver compounds.  Ag⁰ is the metallic or uncharged form of silver found as one of the silver species in nanocrystalline, silver structures.  In solution, the Ag° exists in a sub-crystalline form, less than 8 atoms in size.  Silver nitrate and silver sulfadiazine release silver at concentrations up to 3,200 ppm (silver release from silver sulfadiazine is much slower than that from silver nitrate) but most of this is rapidly inactivated through the formation of chemical complexes.

Early silver formulations compensated for the rapid loss of silver ions by frequent replacement.  Although this was effective, it created problems for healthcare professionals and patients, and resulted in large excesses of silver being delivered to the wound.  In burns units, silver sulfadiazine is commonly applied twice a day and silver nitrate up to 12 times a day.  Repeated applications increase discomfort and wound  trauma.

The nature of the solute also affects the biological activity of silver.  In complex organic biological fluids, continuous concentrations of silver >50 ppm and as high as 60.5 ppm are needed to kill microbes. 

Therefore in wound management, quantities of silver ion should be sufficient to provide sustained bactericidal action.  Acticoat with nanocrystalline silver also provides the Ag⁰ form of silver, which is far less rapidly deactivated by chloride or organic matter than the ionic form.

3. Pro-healing Properties

Although silver in an electro colloidal form, had been reported to improve the healing of indolent wounds in the early 20^th 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 wounds with silver in the nanocrystalline form.  The mechanism, although unknown at present, does not appear to be due to silver’s antimicrobial action.  Controlling the pro-inflammatory cytokines and proteases may be a factor.

4. 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 totally 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.  Silver in the nanocrystal form also decreases wound release of TNFa.