| | The effect of treating infected skin grafts with Acticoat™ on immune cellsAccepted 25 April 2006. 1. Introduction  Control of wound infections in the clinical setting is critical. An ineffective immune system can result in infection which affects graft success, delays wound healing, increases number of surgery procedures, and thereby delays adjuvant therapies and reduces quality of life [1], [2], [3]. Both innate and cell-mediated immunity have important roles in defense against infections and in the promotion of wound healing [4], [5], [6]. Host resistance to bacterial invasions, such as Staphylococcus aureus, a common etiological agent following surgery [7], is thought to be primarily initiated by neutrophils [8], macrophages [9] and natural killer cells [10]. Surgery is known to suppress immunity, thus increasing the risk of infection in the post-operative setting [11], [12]. Acticoat™ is a silver-coated wound dressing that was developed to prevent adhesion, limit nosocomial infection, control bacterial growth, and facilitate burn wound care [13], [14]. Acticoat™ has been shown to have in vitro antibacterial [15], [16], [17] and antifungal properties [18] and in vivo antibacterial activity [19], [20] and because of its moist healing, nonadherent properties has been suggested to be useful as a graft site dressing [21]. In a clinical study, Demling and DeSanti [21] found that rate of re-epithelialization was increased by over 40% when compared to treatment with a 0.01% neomycin and polymixin solution. Faster re-epithelialization under Acticoat compared to moist control dressings has also been shown in a porcine model [22]. Wright et al. [23] compared healing of contaminated full thickness wounds under polyhexamethylene biguanide (PHMB) containing dressings to that under Acticoat dressings. They found that, on day 4, the wounds under the Acticoat dressings contained significantly fewer polymorphonuclear cells (PMNs) and healthier fibroblasts than those under the PHMB dressings. At day 21, they found that the PHMB treated wounds contained high numbers of inflammatory cells and were still open while the Acticoat dressing treated wounds were closed had no evidence of inflammatory cells in the extracellular matrix and a marked reduction in cellularity. This same group [24] reported on the effects of Acticoat dressing and silver nitrate on matrix metalloproteinases, cell apoptosis and healing in a porcine model of full thickness contaminated wounds. They found that contaminated wounds treated with Acticoat developed healthy granulation beds faster than control and silver nitrate treated wounds. At day 4, the Acticoat treated wounds had well vascularized granulation beds containing few PMNs and bacteria with numerous fibroblasts while the silver nitrate treated wounds had only begun to granulate and contained primarily inflammatory cells numerous bacteria and few fibroblasts. The concentration of matrix metalloproteinases (MMP) remained relatively low during the healing process under Acticoat while those treated with silver nitrate and saline had extremely elevated levels. While they did not comment on wound contraction their pictures clearly show that wounds under Acticoat dressings did not contract significantly while those treated with silver nitrate did. They concluded that the Acticoat dressing may play a role in altering or compressing inflammatory events in wounds and in facilitating early phases of wound healing. These benefits are associated with reduced local matrix metalloproteinase levels and enhanced cellular apoptosis. There are anecdotal reports which suggest that the dressing has antipruritic effects suggesting involvement of the immune system [25]. The chemical basis for these improvements in healing and antimicrobial activity are unknown, however it is clear that they are not due to the presence of silver in its most common soluble form, the Ag+ ion. In several studies silver nitrate, a source of silver ions, was used as a control. Fan and Bard [26] showed that Acticoat dressings release at least two forms of silver into solution. Since much of the published data on Acticoat dressing's effects on wounds and bacteria suggest unique biological properties associated with unique silver species and this, in turn, is linked to improved antimicrobial efficacy and wound healing, a study was conducted to determine the effect of Acticoat™, placed on an infected skin graft after surgery, on parameters of immunity. 2. Methods 2.1. Materials and supplies RPMI 1640 culture media and all other culture ingredients were purchased from Fisher Scientific (Edmonton, Alta., Canada). The mitogens Concanavalin A (con A), phorbol myristate acetate (PMA), phytohemmatogluttinin (PHA) and pokeweed mitogen (PWM) were purchased from ICN (Montreal, PQ, Canada). Lipopolysaccharide (LPS) was purchased from Sigma Chemical (St. Louis, MO, USA). Dihydrorhodamine was purchased form Molecular Probes (Eugene, OR, USA). The NK sensitive cell line K562 was purchased from ATCC (Rockville, MD, USA). Triton X was purchased from BDH Chemicals (Toronto, Ont., Canada). The dermatome used to make the wounds was purchased from Padgett Instruments Ltd. (Kansas City, MO, USA) and Neet™ was obtained from Carter Products Ltd (Mississauga, Ont., Canada). The Acticoat™ silver-coated dressings were provided by Westaim Corporation (Fort Saskatchewan, Canada). 2.3. Animals and surgery procedures All procedures were reviewed and approved by the Health Sciences Animal Welfare Committee in the Faculty of Medicine at the University of Alberta and were consistent with Canadian Council on Animal Care guidelines. Twenty-eight female Hartley guinea pigs (350–450 g) were obtained from Charles River Canada (Laval, Que., Canada) and housed in the Health Sciences Laboratory Animal Services vivarium (University of Alberta, Edmonton, Alta., Canada). Following the acclimation period, animals were weighed and lightly anesthetized with isoflurane inhalant. Once anesthetized, dorsal trunk hair was clipped and depiliated with Neet™. Animals were allowed to recover from anesthesia following depiliation. On day 0 the surgery procedure was performed. Animals were premedicated with buprenorphine (0.05mg/kg subcutaneous; SQ), and anesthetized with isoflurane inhalant. The area was prepped with 70% (v/v) ethanol, followed by proviodine solution. Prior to surgery, the proviodine was washed off with sterile saline. The area over the dorsal midline, distal to the scapular area was insufflated with sterile saline and lubricated with sterile mineral oil. Two split thickness wounds measuring 1.5cm×1.5cm×0.33mm were created on either side of the dorsal midline using a dermatome. The skin was obtained from the animal and meshed (1–1.5) to form an autologous split thickness skin graft. The graft was stapled in place over each wound. Both wounds on each animal were not inoculated (Surgery-Noninoculated group, n=8) or inoculated with Staphylococcus aureus at 0.5mL of a 2×107cfu/mL per wound (Surgery-Inoculated group, n=8). Wounds were dressed in either a nonadherent fine mesh dressing, or Acticoat™ silver-coated dressing (Surgery-Inoculated-Acticoat group, n=6), covered by a plastic vapour barrier and bandaged with a 5cm Kling halter wrap. The plastic vapour barrier ensured that the moist dressings did not need to be remoistened during the experiment as the principle mechanism for water loss from such dressings is evaporation. In clinical practice, the use of a vapour barrier over Acticoat dressings will maintain a moist environment for up to 7 days. Following surgery, animals were allowed to recover under an infrared heat lamp until they reached sternal recumbancy. Animals were returned to clean caging and recovery monitored for 24h. Analgesia was maintained with buprenorphine (0.05mg/kg SQ). Guinea pigs were weighed daily throughout the post-op experimental period. In order to determine the immunological response of animals not undergoing anesthetized surgery, a group of guinea pigs was singly housed, handled and weighed daily but did not undergo anesthesia and surgery procedure (Nonsurgery Control group, n=6). Wounds were observed on a daily basis to note any significant erythema, oedema or purulent discharge. On day 5, when the Acticoat treated grafts were expected to be greater than 50% healed [21], guinea pigs were euthanized with CO2. Blood was collected by cardiac puncture into sodium heparin Vacutainer® tubes (Becton Dickinson Ltd.) for determination of neutrophil oxidative burst and spleens were aseptically collected. 3. Results 3.2. Wound appearance None of the wounds in this study were excessively inflamed at the termination time of 5 days. There was no observation of excessive erythema, oedema or purulent discharge. 3.4. Natural killer cytotoxicity All surgery groups (Surgery-Inoculated, Surgery-Noninoculatedand Surgery-Inoculated-Acticoat) had significantly lower (p<0.001) percent specific lysis of target cells by splenocytes at every effector:target ratio compared to the Nonsurgery control group (Fig. 1). At the highest target cell ratio (100:1) the percent specific lysis by splenocytes from the Surgery-Inoculated-Acticoat group did not differ from the Surgery-Noninoculated group and was significantly higher than the Surgery-Inoculated group (Fig. 1). 4. Discussion In studies with humans, the frequency of burn wound sepsis and secondary bacteremias arising from infected burn wounds have been shown to be less frequent with the use of Acticoat™ bandages compared to those treated with silver nitrate [13]. Porcine donor sites treated with Acticoat, were shown to heal in 70% of the time of petrolatum gauze. Demling and DeSanti [21] showed a 40% increase in the rate of meshed autograft re-epithelialization when Acticoat is used versus a standard antibiotic solution, and that Acticoat treated grafts were 100% healed after 7 days of treatment. Innes et al. [33] demonstrated that Acticoat dressings were inferior to a foam dressing in the treatment of donor sites when large amounts of water (up to 30mL/in.2/day) were added to the dressing, a quantity that would be expected to macerate the wound. Perhaps more significantly, Wright et al. [23], [24] showed that the Acticoat dressing, while having very potent antimicrobial effects, appears to have other cell altering properties including anti-inflammatory activity. The dressing leads to early healing as a result of the minimization of potentially detrimental inflammatory effects through the suppression of the release of matrix metalloproteinases and the induction of apoptosis. It is this novel combination of biological activities at the molecular and cellular level that leads to the idea that the protection offered by Acticoat™ may be partially due to enhanced immune functions that play a role in defense against common wound infections. This study confirms the immunosuppressive effects of surgery and presents data to suggest that Acticoat™ treatment of a skin graft wound inoculated with S. aureus may be beneficial to NK and neutrophil function. There were no weight loss differences between the various surgery groups suggesting that the various treatments had no significant effect on morbidity. In a rodent study weight loss was the single largest predictor of gross morbidity when they were inoculated with bacteria via a 20% total body surface area burn injury [20]. The lack of any significant observations regarding the characteristics of the wounds indicates that the combination of inoculum level and species of S. aureus used were not sufficient to cause morbidity in this study, however, the presence of bacteria elevated the unstimulated response of both splenocytes and neutrophils above that observed in the Surgery-Inoculated-Acticoat and Surgery-Noninoculated groups, respectively, as well as the Nonsurgery control group. The high unstimulated response by both neutrophils and lymphocytes suggests in vivo activation of immune responses in the Surgery-Inoculated group. Elevated neutrophil oxidative burst has been reported following minor surgery procedures [34] as well as in acute infections [35]. Cytokines and circulating factors present during an infection have been shown to prime neutrophils and increase their response when stimulated [36]. Taken together, this suggests a general elevation of immune responses that may have occurred in vivo in the presence of an infection. Furthermore, the infected group exhibited elevated [3H]-thymidine incorporation in the presence of PWM, primarily a B cell mitogen [37]. PWM is mitogenic to both T and B cells but, unlike LPS, requires interactions with MHC II for mitogenesis to occur [38], [39], [40]. All other mitogens tested were similar to controls, therefore, this effect may be due in part with the way PWM stimulates cells or how the presence of S. aureus influences this interaction [41]. [3H]-thymidine incorporation estimates cell division and not immunoglobulin secretion or differentiation of B cells [40], [42], therefore, B cell function specifically, was not measured in this study. The surgery procedure was suppressive to mitogen stimulated lymphocyte proliferation and NK cells, both of which have been well documented following surgery [11], [12], [29], [43], [44]. Applying the Acticoat™ bandage did not appear to modify the suppressive effects of surgery on mitogen stimulated proliferation of splenocytes. Natural killer cell cytotoxicity of splenocytes however, was improved over the infected group when the Acticoat bandage was applied. Natural killer cells are able to activate both innate and adaptive immune responses and also directly contribute to host resistance. NK cytolytic activity is greatly increased during bacterial infection [45] and, of relevance to this study, they are able to interact with epithelial dendritic cells [46]. This study shows for the first time that applying the Acticoat bandage improves NK cell cytotoxicity which may offer an important defense against wound infection. Neutrophils from the Acticoat group also produced the highest oxidative burst after 5min which suggests an enhanced ability of neutrophils to respond to a challenge. Neutrophils are the first type of defensive cell at the site of a wound and although those from the local wound area were not directly studied, the observations of higher neutrophil responses by the inoculated and Acticoat treated groups suggests effective antibacterial function. Superoxide production by neutrophils is an important defense mechanism against invading microorganisms in the wound area. The authors recognize that higher neutrophil responses have been associated with damage to healthy tissues, however in light of the human studies [13], [47] and the lack of any obvious deleterious effect on the wounds in this study and given no difference in Acticoat responses by 15min post stimulation, we suggest this correlates to improved bactericidal function. It is not clear why Acticoat would have these types of effects. It may lie in the amount of silver absorbed or the species released or a combination of both factors. Systemic absorption of silver from Acticoat has been measured in premature neonates [48] at levels of <5.4–107μg/L, although they point out that the higher level was in an infant that was previously treated with silver sulfadiazine. The other two neonates in their study had serum silver levels less than 5.4μg/L. Others have studied silver uptake in adults from silver sulfadiazine where concentrations from 50 to 307μg/L have been reported [49]. Given the low concentrations of silver taken up by neonates, who have immature skin that is much more permeable than mature skin, it is unlikely that systemic silver has any effect on the data in collected in this study. However, Fan and Bard [26] have shown that Acticoat releases at least one other silver species into solution that other forms of silver do not. They clearly demonstrated the release of Ag0 which appears to be a unique form of silver that may exist as a cluster structure in solution. It is believed that it is the presence of unique species that makes the large differences in speed and quality of wound healing previously reported [21], [22], [23], [24]. The Ag0 structure may be the key to explaining many of the biological properties of noble metals in general. Gold is a well known anti-inflammatory agent used in the treatment of rheumatoid arthritis and platinum, as the organometallic complex cisplatin, has strong antitumour properties. These materials have unique unexplained biological properties that may be linked to the activity reported here and elsewhere for nanocrystalline silver [24], [50], [51]. Chemically and physically these materials have many similar properties including structure at the crystal level and these links should be investigated. In conclusion, application of an Acticoat™ bandage to a post-operative infected wound, improved NK cytotoxicity, and produced neutrophils with a more robust oxidative burst when challenged in vitro. 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PII: S0305-4179(06)00162-8 doi:10.1016/j.burns.2006.04.027 © 2006 Elsevier Ltd and ISBI. All rights reserved. | |
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