Characterization and evaluation of silver release from four different dressings used in burns care
Introduction
Ionic silver (Ag+) has been widely used as an antimicrobial in the treatment of recent wounds, skin ulcers and burns since mediaeval times and was the pivotal drug in these fields until the discovery of synthetic antibiotics [1]. During the Second World War the employment of antibiotics became common practice in medicine so the interest in using silver to prevent bacterial infections disappeared. Although antibiotic drugs remain of great importance, their overuse rapidly caused the rise of resistant bacteria. So silver has once again become a main therapy in wound healing and burns therapy [2]. In 1965 Moyer treated burns with dressings moistened with 0.5% silver nitrate (AgNO3) solution [3], and in 1967 Fox synthesized silver sulphadiazine (Ag-SD), by combining AgNO3 with sulphadiazine, a sulpha-drug that had recently been discovered. Currently Ag-SD is still commercialized in the form of a 1% (w/w) water soluble cream, and is one of the most employed first treatment drugs in burns centres worldwide [4]. At the end of the 1990s, several Ag containing dressings appeared in commerce. The dressings are typically composed of a polymeric scaffold impregnated with a Ag salt or metallic Ag in nanoparticulate form, and they exhibit fast and broad spectrum antibacterial activity against both Gram positive and negative bacteria [5], [6], [7]. With respect to AgNO3 and Ag-SD impregnated dressings, the new Ag containing dressings are less irritating and need to be changed with a lower frequency, so it is possible to reduce the pain suffered by burns patients caused by frequent changes [8], [9]. Silver impregnated dressings are declared to be safe for patients and are non-cytotoxic [10], [11] even if recent studies have speculated that there are possible toxic effects on human fibroblast and keratinocytes [12], [13]. The use of these new Ag-based dressings is thought to possess another important advantage: the blue discolouration of skin (argyria), which is the main side effect associated with Ag topical use, is rare and generally transient (not permanent) [10], [14]. Despite the wide use of these dressings, systematic studies about Ag content and release are still limited [15], [16], [17], and in particular, in most of them, the release properties were investigated in ultra pure water or in bacterial growth medium [18], [19]. In most cases the experimental conditions and the media employed to estimate the release of silver were unable to simulate the complex wound environment and in some cases the release experiments were conducted using dynamic dissolution tests [20], or transferring the dressings into fresh media every day, for a week [18], [19], forcing the release above that expected on a static patient. Thus the data collected are probably unrealistic, and are mostly available for only a small number of time points without clear reproducibility data [15], [16], [17].
In this research work we have evaluated the silver release from four Ag-based dressings used for the treatment of burns, namely ACTICOAT™ Flex 3, ACTISORB® Silver 220, AQUACEL® Ag and Mepilex® Ag. The release was assessed in three matrices of increasing complexity: ultra pure water, a physiological saline solution and human serum substitute. These matrices are able to provide an approximation of the possible chemical environments with which Ag can react during routine application of dressings with different levels of accuracy. Ultra pure water is the simplest matrix, and physiological saline solution simulates the chloride rich wound environment [21], [22], in which a considerable fraction of Ag is expected to be complexed by chloride and probably precipitates as insoluble AgCl. The serum substitute was chosen as it contains human recombinant albumin, transferrin and insulin in concentrations that reflect those observed in real human serum. This solution was used to assess if the presence of proteins could enhance Ag+ release and solubility, by acting as a complexing agent [23] or by formation of protein coronas [24] that are thought to affect the bioavailability of nanoparticles [25]. To our knowledge, this is the first time that this complex solution has been employed to verify the release of soluble Ag from commercially available dressings. The amount of Ag released has been quantified by inductively coupled plasma mass spectrometry (ICP-MS), and the structure of the dressings was characterized using scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) before and after the release experiments.
Section snippets
Sample dressings
Sample dressings were obtained from the University Hospital of Padova (Italy). ACTICOAT™ Flex 3 (Smith & Nephew, Milan, Italy) dressing is a flexible polyethylene cloth coated with nanocrystalline Ag particles in a concentration between 0.69 and 1.64 mg/cm2. The manufacturer claims that ACTICOAT™ FLEX 3 provides an effective antimicrobial barrier for up to 3 days so this period is recommended as the maximum application time. Mepilex® Ag (Mölnlycke Health Care, Gallarate, Italy) consists of a
Results
The Ag concentration in the dressings was determined as mg/g (or μg/g) and then the results were converted to mg/cm2 (μg/cm2). For each dressing the Ag concentration was found to be in agreement with that declared by the producers and Ag was demonstrated to be homogenously dispersed over the entire surface area. The average Ag concentrations were: 1.379 ± 0.091 mg/cm2 for ACTICOAT™ Flex 3; 0.111 ± 0.004 mg/cm2 for AQUACEL® Ag; 0.993 ± 0.078 mg/cm2 for Mepilex® Ag and 26.6 ± 1.3 μg/cm2 for ACTISORB® Silver
Discussion
In this work we investigated the amount of silver released and the release profiles from four Ag-based dressings, the release properties of these products were compared in three matrices of increasing complexity. The aim of this work was to clarify the chemical aspects of Ag release and to provide the medical community experimental evidence to support their choices when deciding which Ag-based product should be used when confronted with an array of different medical cases. We hope that this
Conclusions
The results of the release experiments carried out in this research work attest that for all the dressings (apart from Mepilex®) the highest release rates are found in serum substitute and the lowest release rates are in saline solution. The low apparent release rates in saline solution are due to the formation of insoluble AgCl that is removed after centrifugation of the sample. Re-solubilization and analysis of the precipitate demonstrates that higher amounts of Ag were released but
Conflict of interest statement
There are no conflicts of interest to declare.
Acknowledgements
The authors are grateful to the Italian Ministry of Instruction, University and Research for financial support through project MIUR-FIRB number RBFR08M6W8. Dr. Paolo Guerriero and Dr. Federica Fenzi, Institute of Inorganic Chemistry and Surfaces of the Italian National Research Council, Padua, Italy, are acknowledged for their help in SEM-EDS analysis. ELGA LabWater is acknowledged for providing the PURELAB Option-Q and Ultra Analytic systems, which produced the ultra pure water used in these
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