EUROPEAN TISSUE REPAIR SOCIETY
CONCEPTS IN CLINICAL WOUND HEALING |
EUROPEAN TISSUE REPAIR SOCIETY CONCEPTS IN CLINICAL WOUND HEALING |
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THE ROLE OF SILVER
Recent advances in biotechnology and original research have provided unique opportunities to develop dressings which are closely tailored to the type of wound to be treated. They are biocompatable and are proving to be of great benefit in advancing healing in difficult wounds whilst alleviating patient discomfort and impaired mobility. At least ten new sustained silver-release dressings have reached late stages in development or are presently marketed in Europe and elsewhere. They vary greatly in composition but are variously designed to cope with moderately to heavily exudating wounds with unsociable odours, and pain and discomfort. Silver is presented to the wound as a broad spectrum antibacterial with claims for efficacy in the elimination of Gram positive and Gram-negative bacteria, yeasts/fungi, and the methicillin-resistant Staphylococcus aureus and vancomycin-resistant infections. Other materials present include polyurethane foam or lamina, hydro-colloids, charcoal-containing materials, nylon cloth or other substances to control odours and excessive wound exudates whilst maintaining a suitably moist environment to maximise healing. The term 'nanocrystalline' silver has been introduced and is held to represent a new entity in wound management. Silver as an Antibacterial Agent As a metal, silver is relatively inert and poorly absorbed
by mammalian or bacterial cells. However, in the presence of wound fluids
or other secretions, it readily ionises and becomes highly reactive in
binding to proteins and cell membranes. The silver ion (Ag+) is absorbed
by the bacterial or yeast cells and is lethal in sensitive strains. The
biocidal effects of silver are complex, and different organisms respond
to silver to varying extents. Evidence provided from the development of
silver:copper filters in the sterilization of hospital water systems,
suggests that silver is accumulated preferentially in sensitive bacterial
strains and that concentrations of 105-107 ions per cell are lethal. Early
pharmacologists coined the term oligodynamic to refer to the ability
of sensitive bacteria to absorb and concentrate Ag+ from dilute solutions.
They suggested that the lethal concentration of ion in a cell was equivalent
to the number of bacterial cell enzymes present. Studies designed to evaluate the efficacy of silver nitrate,
silver sulphadiazine or the newer sustained silver release dressings,
have routinely assessed their effect on the type and severity of infections
present in wounds. Few have looked at the mechanism(s) of bactericidal
action or discussed how or why different organisms exhibit varying sensitivity
to the silver ion. Microbiological studies illustrate that the 'activated'
silver ion (Ag+ or other species) can exert its lethality through action
on the bacterial cell membrane (envelope) or binding to and inactivating
intracellular proteins/enzymes and nuclear DNA. Many studies have examined the biocidal action of silver
ion and silver-release dressings on species of bacteria or yeasts in
vitro. An example is provided by a bioactive glass containing silver
oxide as an antibacterial developed for use in dentistry or orthopaedic
medicine. This was highly effective against Pseudomonas aeruginosa,
Staphylococcus aureus and E.coli at concentrations of 0.05-0.2
mg/ml, Ag+ leaching from the glass matrix was the active agent rather
than any other effect (changes in pH, ionic strength, etc.) attributable
to other biomaterials present. In vitro studies have provided evidence
that this bacticidal effect is attributable largely to the binding of
the silver ion to free sulphydryl groups in the bacterium or on its surface.
Thus silver sulphadiazine and two other silver-containing products were
shown to inhibit the growth of Candida albicana or E.coli
through inactivation of the enzyme phosphomannose isomerase. Where the
enzyme was mutated to replace the free cystine moiety with alanine (lacking
-SH groups), inhibition was not seen. More substantive information on the bactericidal action
of silver relates to its accumulation in the bacterial cells and its opportunity
to interact with the cytosolic proteins, mitochondrial enzymes and nuclear
DNA or RNA synthesis. Substances in the medium (or it the wound bed) that
chelate free silver ion or precipitate it as an insoluble sal, inhibit
bacteriostasis. Thus sodium chloride (as possible found in wound exudates)
has been shown to inhibit the antibacterial action of silver nitrate by
precipitating the silver as insoluble silver chloride. On the other hand,
EDTA or EGTA, have been shown to enhance the biocidal effect of silver
nitrate, possibly through chelating silver binding substances. Silver and the Skin Wound In the wound bed, silver ion is biologically active and
avidly combines with proteins, cell surface receptors (and sulphydryl
groups) and wound debris. A contraindication for silver nitrate use in
wound prophylaxis, is its profound ability to stain everything black.
Although silver nitrate is an effective antibacterial agent and is still
available, the tissue discoloration is usually unacceptable these days
except in the treatment of severe burns. Although silver sulphadiazine
and the new sustained-silver release dressings liberate silver ion into
the wound bed, discolouration of the tissue is rarely a problem with silver
sulphadiazine, and has not been recorded so far with products like Acticoat,
Actisorb, Contreet, Arglaes or Avance. The reasons for this are not clear
at the moment, but possibly relate to the nature/species of silver ion
released and its reactivity with proteins in the wound bed. Absorption of silver from wound care products and dressings
by cells of the wound margin is not documented in most clinical studies,
but regular mention is made of improved patterns of re-epithelialisation,
wound closure and healing. This suggests that the silver ion is having
a direct effect on the regenerating epidermis, or it is enhancing the
local microenvironment in some way to promote the healing process. Reduced
wound pain and patient discomfort might suggest that the silver is acting
also on the inflammatory/granulation tissue phase of wound repair and
upon the polymorphonuclear cells entering the site. However, we do know
through experimental and clinical work, that silver permeating into the
wound bed is taken up by epidermal cells at the wound margin and is accumulated
in the wound debris and passes into the peripheral circulation to be deposited
in the liver and kidney, with some voided in the urine. Improved healing in rat wounds exposed to silver nitrate or silver sulphadiazine has prompted research into the mechanism of action of the silver ion in epithelial cells. Evidence was provided through immunocytochemical evaluation of key metal-binding metallothioneins, to show that silver induced these proteins and enhanced the local concentrations of zinc and copper. Both metals are essential micronutrients involved in epithelial cell proliferation. Increased zinc leading to enhanced production of RNA and DNA-synthetases, matrix metalloproteinases and other essential enzymes in the wound bed are held to contribute to the improved healing observed. Interestingly, increased calcium levels have been observed in experimental wounds treated with silver. The implications of this are unclear at the moment, but we do know that calcium is an essential component of haemostasis as Factor IV, and that increases in calcium in the wound margin are a normal feature of healing in acute skin wounds. Calcium serves as a central modulator at several different levels in wound repair and the importance of calcium gradients in homeostasis in the skin are documented. Clearly, at a time when calcium alginates are being introduced into wound dressings with or without silver as an antibacterial agents, there is an urgent need to study the interaction between the two metals in wound repair. Clinical Aspects of Sustained-Silver Release Dressings in Wound Healing Sustained silver release dressings have been developed
over the past fifteen years. The dressings are increasingly tailored as
broad spectrum antibiotics and barriers to infection, but are designed
to handle the wound exudates, offensive odours and patient discomfort
commonly associated with severe surgical wounds, graft and donor reactions,
and chronic or delayed healing wounds including varicose ulcers, leg ulcers
and diabetic wounds. Manufacturers stress the value of their products
in treating these debilitating wounds emphasising the value to the silver
in alleviating infections whilst improving conditions in the wound bed
to promote, advance or 'kick start' the healing process. Published clinical studies demonstrating the benefits
of the new silver release dressings are limited at the moment, with patients
selected for study varying greatly in age and clinical condition. The
wound types discussed range from burn wounds, graft and donor sites, chronic
ulcers, decubitus ulcers, toxic epidermal necrolysis and diabetic wounds
to severe traumatic lesions. The underlying pathogenic mechanisms differ
greatly and patients vary in age, health status and duration of the clinical
problems. Comparison of the merits of the various dressings are understandably
difficult, but in each case, infection was a recognised problem, occasionally
with methicillin-resistant Staphylococci (MRSA) and vancomycin-resistant
bacteria being identified. Some wounds were associated with immuno-suppression
in affected patients, but no evidence has been provided so far to show
that silver influences the immuno-suppressed state commonly seen in burns.
(Cerium nitrate as used in burns wound therapy with or without silver
sulphadiazine (Flammacerium), can suppress immune reactions attributable
to substances like lipopro-teins liberated in wound sites.) In summary,
there is undeniable evidence that all the sustained silver release dressings
provide a highly commendable antibacterial activity with barrier function
against re-infection, with efficacy closely related to the level of silver
released and the duration of action. Most reports appreciate the advantages
of the hydrocolloid and polyurethane foam and other components of the
dressings in absorbing and managing wound exudates and odours, whilst
controlling the moisture content in the wound bed to stimulate wound healing.
With few exceptions, patient comfort and mobility is greatly improved. Greatest clinical experience has been gained with Acticoat, which has been developed over the past 15 years for use in chronic wounds, autografts, burns, epidermal necolysis. Acticoat and related dressings have consistently demonstrated antibacterial action and barrier function, reduction in inflammatory mediation and stimulation of healing responses. Actisorb Silver 220 dressing is claimed to have particular advantages in eliminating wound odour through the charcoal component, but in other respects it is successful in suppressing granulation tissue, purulence and wound exudate. Additionally, it has proved highly beneficial in alleviating over-granulation and leakage in percutaneous, endoscopic gastronomy sites. Clinical studies with reference to case studies are available also to substantiate the value of other sustained silver release dressings like Arglaes in treating major surgical wounds, Con-treet Foam and Contreet Hydrocolloid in moderate to heavy exudating wounds, and Avance in the therapy of painful, macerating wounds with recurrent infection. Although useful comparative studies are available to show the value of the sustained silver release dressings in relation to older silver medicaments, the relative benefits of Actisorb, Acticoat, Arglaes, etc., in treating wounds of a comparable type in impartial investigations are not presently appreciated. Contraindiations of Sustained Silver Release Dressings Silver has been a choice antibacterial for use in wound dressings and therapeutics on account of its acknowledged low toxicity. Argyria as regularly encountered with silver nitrate and occasionally with silver sulphadiazine, does not seen to be a problem with Acticoat, Actisorb, Contreet, etc. However, the principle anxiety of silver allergy will remain. Silver allergy or hypersensitivity does affect a small proportion of the population and case reports relate to the use of silver nitrate as a topical antibacterial. Although not specifically identified so far, the possibility of allergic reactions arising through the use of newer silver wound treatments should be considered, and may prove a contraindication for their use in some patients. Other complications including leucopenia, bone marrow toxicity and renal or hepatic damage through silver deposition, as seen rarely with silver nitrate of silver sulphadiazine, are likely to be of marginal significance. Future Research and Development Recent research and new developments in wound dressings have provided clinicians with greatly improved methods for treating chronic and complicated wounds with the high risk of infections. Whilst clinical trials provide unequivocal observations on the advantages and benefits of the various dressings available, from a scientific and regulatory view, it is desirable now to investigate mechanisms of action and the fate of the silver ion. Animal models have provided considerable insight into mechanisms of action of silver and other wound medicaments. These could now be fruitfully employed to investigate such features as silver accumulation in wound sites in relation to healing patterns, patterns of silver metabolism in relation to trace metals like zinc and calcium, and the route and rates of silver excretion. Good comparative studies of the relative benefits of Acticoat, Arglaes, Actisorb, Contreet and Avance in a standard wound (e.g., the pig) can be of useful prognostic value. (A detailed bibliography on the role of silver and silver containing dressings in wound care and as antibacterial agents is available for reference purposes.) Alan B.G. Lansdown, PhD, FRCPath, FIBiol, Mimgt |
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Designed by the eDoodle group
Studies
on wound healing in recent years have increasingly focused upon the importance
of wound bed preparation and the relevance of creating a conducive environment
for epidermal regeneration and dermal repair. The value of debridement
and maggot therapy in removing the necrotic burden is recognised. It is
appreciated that chronic and delayed healing wounds are notoriously prone
to and that the elimination of infections like Pseudomonas aeruginosa,
Staphylococcus aureus, Candida albicans and other organisms is of
prima facie importance in wound healing. Silver as silver nitrate, colloidal
silver or silver sulphadiazine cream has been a choice antibiotic for
wound care for many generations and numerous clinical studies have substantiated
its merits in treating venereal infections, warts, chronic ulcers and
surgical incisions. Clearly, after a highly successful meeting of the
European Tissue Repair Society in Cardiff in 2001 and the publication
of three issues of 'The Silver Supplement' to the British Journal of
Nursing, it is clear now that we have entered the new phase of 'sustained-silver
release dressings'.