Fw: [mscured] CONCEPTS IN CLINICAL WOUND HEALING

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Sent: Wednesday, September 08, 2004 4:12 PM

Subject: [mscured] CONCEPTS IN CLINICAL WOUND HEALING

> CONCEPTS IN CLINICAL WOUND HEALING

>

>

> Look this up Oligodynamic Ag+

>

> THE ROLE OF SILVER

> Dr Alan B.G. Lansdown, Skin Research and Wound Healing Laboratory,

> Imperial College of Medicine, London

>

>

>

> 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'.

>

>

> 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 resistant strains of bacteria are a continuing problem in

> wound care despite many claims in the literature to the contrary.

> Accumulating evidence indicates that the bactericidal activity of

> silver is directly related to the amount of silver accumulating

> within the bacterial cell and its ability to denature or otherwise

> impair physiological processes. Silver-sensitive strains of

> Pseudomonas stut-zeri have been shown to produce a higher emission of

> hydrogen sulphide gas than the resistant strains. Slawson et al

> (1990) reviewing the interactions between bacteria and silver

> emphasised the influence of silver on mitochondrial activity and

> other energy dependant processes. They drew attention to the role of

> plasmids (cytoplasmic particles) in bacterial resistance. Further

> work revealed that silver resistance is related not only to the

> existence of plasmids in the bacterial cell, but their structure and

> type. Starodub and Trevors (1989) demonstrated two large plas-mids in

> silver resistant strains of E.coli isolated from a burns wound

> patient and their propensity to bind silver ion. They noted that by

> heating, they could alter the silver binding properties of these

> plasmids and influence bacterial resistance to silver. Transmission

> electron mi-croscopy and energy dispersive X-ray analysis of whole

> cell mounts from actively growing cultures confirmed that resistant

> strains did not accumulate silver whereas the sensitive strains

> exhibited numerous electron dense particles. In this strain of E.coli

> at least, the plasmid coded 'pJTI (83kb) seemed to be primarily

> responsible for silver resistance. Similar patterns of plasmid-

> modulated silver uptake are known to control the sensitivity of

> bacteria like Acenitobacter baumannii and Salmonella sp., but further

> work is urgently needed to examine mechanisms of silver sensitivity

> in bacterial and fungal strains commonly found in skin wounds and

> ulcers.

>

> Silver and the Skin Wound

> The literature is replete with clinical trials purporting to shown

> the benefits of silver therapeutics and silver-release dressings on

> wound repair and regeneration through its antimicrobial efficacy.

> Little is published, however, to show how the released silver ion

> influences the wound bed, or to what extent it is metabolised or

> deposited in the tissue. Nevertheless, silver is absorbed into the

> wound site, some serving an antimicrobial function, with the

> remainder being taken up by cells at the wound margin or diffusing

> into the circulation. It maybe that some of the silver ion is

> absorbed into the epidermis in the form of a reservoir and then

> released into the surrounding tissues, but there is evidence that

> silver uptake tends to be higher in partial thickness wounds where

> granulation tissue is more extensive.

>

>

> 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.

> Experimental studies in laboratory animal models have greatly aided

> our understanding of the action of silver in the wound. Porcine burn-

> like wounds, for example, have been shown to absorb silver from

> silver sulphadiazine leading to the preservation of 'viable' dermal

> tissue, improved wound contraction and activation of dermal myo-cytes

> (fibroblasts). In rat and guinea pig wounds, silver nitrate and

> silver sulphadiazine advanced wound repair and neovascularisation

> without obvious contraindica-tions.

>

>

> 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

> Skin Research and Wound Healing Laboratory,

> Department of Clinical Chemistry,

> Division of Investigative Sciences,

> Imperial College of Medicine,

> St s Road,

> London, W6 8RP

>

>

>

>

>

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