A Scientist’s Perspective on Silver Oxysalts: Chemistry Can Help a Wound Progress

Inflammation is a crucial part of wound healing. When a wound occurs, neutrophils and macrophages are recruited to the site to remove pathogens, foreign material, and devitalized tissue. Once the wound is cleared of these substances, inflammatory cell levels diminish until healing is complete. However, in chronic wounds inflammation is heightened and prolonged. Increased numbers of neutrophils and macrophages persist within the wound. These inflammatory cells secrete a cocktail of proteinases, proinflammatory cytokines, and reactive oxygen species (ROS), including superoxide anions (O₂-) and hydrogen peroxide (H₂O₂), that sustain inflammation and cause tissue damage. In turn, tissue damage supports microbial growth; consequently, infection is a frequent complication associated with chronic wounds. In an attempt to clear infection, additional inflammatory cells are recruited to the wound, leading to a cycle of elevated inflammation and causing tissue damage that supports microbial growth which, in turn, increases inflammation, exacerbating the hostile wound environment and inability to heal.

A wound stuck in the inflammatory stage of repair depletes the tissue of vital oxygen, an essential element in the generation of energy. During healing, demand for energy and subsequently oxygen to generate this energy is increased. Inflammatory cells consume high levels of oxygen; during phagocytosis, these cells utilize oxygen in the production of superoxide ions and hydrogen peroxide.¹Infection exacerbates the problem, because aerobic bacteria consume oxygen within the wound. Thus, stalled or infected wounds often are deprived of vital oxygen.

Therefore, antimicrobial therapies are paramount in the fight against wound infection when the host immune response is failing. These antimicrobial therapies need to be powerful enough to combat recalcitrant processes such as the development of biofilms that show increased tolerance to the host immune response and antimicrobial therapies. However, the potent nature of the antimicrobial therapies must not adversely affect the wound environment. Dressings containing silver oxysalts (Ag₇NO₁₁; Crawford Healthcare, Doylestown, PA) exhibit superior antimicrobial activity against both planktonic and biofilm-embedded microbes as compared to traditional silver dressings.^2,3 The chemistry of silver oxysalts is unique; unlike traditional silvers that release Ag¹⁺, highly reactive forms of silver (Ag²⁺ and Ag³⁺) are generated when silver oxysalts come into contact with fluid.

Silvers have a long-standing history in the management of wound infections; however, concerns have been raised over their cytotoxicity and the effects they have on healing when infection is not present. Recently, the effects of silver oxysalts on healing independent of infection were assessed.⁴ Silver oxysalts were added to the culture media of fibroblast and keratinocyte scratch wound assays. No effect was observed on the closure of fibroblast scratch wounds with the addition of silver oxysalts; however, keratinocyte scratch wounds treated with silver oxysalts healed faster. When silver oxysalt dressings were applied to uninfected mouse wounds, the wounds healed faster, showing a reduction in wound area, increased reepithelialization, and decreased inflammation.⁴

An examination was conducted of how silver oxysalts promote healing when infection is not present. Silver oxysalts exposed to fluid are thought to break down and generate oxygen. These silver compounds were added to serum and the level of oxygen within the serum was measured. Of the silver compounds tested, only silver oxysalts generated oxygen. In the wound environment, this oxygen may provide vital energy to the numerous cell types that require additional energy for effective repair. In a chronic wound, the addition of oxygen directly to the wound tissue may be sufficient to shift the wound out of a nonhealing state.

Silver oxysalts also may promote healing through the ability to breakdown H₂O₂. Silver is a known catalyst of H₂O₂, breaking it down into oxygen and water. H₂O₂, produced by neutrophils and macrophages, is the primary mechanism for killing bacteria; however, this process causes severe tissue damage. During normal wound healing, enzymes rapidly detoxify H₂O₂.⁵ In chronic and infected wounds, levels can become unregulated. The ability of a variety of silver dressings to catalyze the breakdown of H₂O₂ was assessed. Only dressings containing silver oxysalts were able to catalyze the breakdown of H₂O₂ to oxygen and water. In recent years, the regulation of ROS through antioxidants and antioxidative enzymes has been examined as a mechanism to reduce oxidative stress-induced tissue damage and promote healing.⁶ The ability of silver oxysalts to breakdown H₂O₂ may rebalance redox signalling and create a less hostile wound environment to support repair.

These recent studies have shed light on the mechanisms of action of silver oxysalts. Despite their potent antimicrobial efficacy, silver oxysalts do not adversely affect healing independent of infection. On the contrary, silver oxysalts promoted many aspects of wound repair when infection was not present (see Figure).

The ability of silver oxysalts to directly produce oxygen and to catalyze the breakdown of H₂O₂ to oxygen and water may create a more favorable wound environment that is sufficient to shift a stalled wound out of the inflammatory phase and progress to healing.

Fresh Views of Silver is made possible through the support of Crawford Healthcare, Doylestown, PA. The opinions and statements of the clinicians providing Fresh Views on Silver are specific to the respective authors and not necessarily those of Crawford Healthcare, OWM, of HMP. This article was not subject to the Ostomy Wound Management peer-review process.