A Scoping Review of the Methodology Used in Studies of Genetic Influences on the Development of Keloid or Hypertrophic Scarring in Adults and Children After Acute Wounding

Significance: Keloid and hypertrophic scarring are common following acute wounds. However, the variability in scarring outcomes between individuals and in particular, the association between genetic factors and scarring, is not well understood. This scoping review aims to summarize the methodology used in studies of genetic influences on the development of keloid or hypertrophic scarring in adults and children after acute wounding. The objectives were to determine the study designs used, the characteristics of participants included, the tools used to assess scarring and the length of follow-up after wounding. Recent Advances: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Excerpta Medica Database (EMBASE), Web of Science, Biosciences Information Service (BIOSIS), Prospective Register of Systematic Reviews (PROSPERO), The Human Genetic Epidemiology (HuGE) Navigator (database of genetic association studies), and the genome-wide association study Catalog were searched from January 2008 to April 2020. Cohort studies and case-control studies that examined the association between one or more genetic variations and the development of keloid or hypertrophic scarring were eligible for inclusion. A narrative synthesis that grouped studies by wound type was conducted. Critical Issues: Nine studies met the inclusion criteria (five in burns, four surgical wounds, and none in other types of acute wounds). Seven assessed hypertrophic scarring, one keloid scarring, and one both scar types. Seven studies used a prospective cohort design. All studies used subjective methods (clinician or patient observation) to assess scarring. There was considerable variation in how scar scales were operationalized. Future Directions: This review identified a small body of evidence on genetic susceptibility to scarring after acute wounding. Further studies are needed, and in a wide range of populations, including patients with wounds caused by trauma. </p

First aid treatment of burn injuries: Optimum treatment and mechanisms of action

There are many public health organizations with guidelines concerning the best first-aid treatment for burn injuries. The Australian and New Zealand Burn Association recommends that a burn wound should be cooled with tap water (8-20°C) for 20 minutes, up to three hours after the injury has occurred. However, the evidence that these guidelines are based on is inconclusive and contradictory. As a result of the conflicting published data, there is controversy over whether ice water or ice may confer any beneficial wound healing effects, and what temperature of water is optimal. In the wider community there are also many different alternative therapies believed to be beneficial for the treatment of burn injuries which do not have much evidence to support their use. In this study, patients were found to use agents such as Aloe vera, tea tree oil dressings, butter, toothpaste, papaya ointment and moisturizer on the burn wound. The aim of this work was to review the current field of first-aid treatment for burn injuries and obtain evidence for the optimum first aid treatment using a good animal model, with clinically relevant assessments of wound healing and scar formation. The mechanisms behind the best first aid treatment were also investigated in an effort to better understand and identify the factors involved in optimal wound healing. Studies showed that cool running water at 15°C and 2°C improved the speed of wound healing, gave a better cosmetic outcome and decreased amounts of scar tissue compared to untreated controls. Other treatments Aloe vera, tea tree oil dressings, ice and saliva did not improve wound healing compared to untreated controls. All cold treatments acted to decrease the subdermal temperature, however as the running water was beneficial for wound healing whereas the ice was not, this suggests that the running water acts through other non-thermal mechanisms. Further studies showed that immediate treatment with 15°C water for 20 minutes duration significantly improved the re-epithelialization for 2 weeks post-burn and decreased the distribution of scar tissue compared to untreated controls, however durations as short as 10 minutes and delays of treatment for 1 hour (and perhaps longer) were also beneficial. An audit of first aid used by pediatric patients demonstrated that although 86.1% of patients used first aid, only 12.1% applied the recommended first aid treatment of cold water for 20 or more minutes. For those that did use correct first aid, re-epithelialization time and number of hospital visits were significantly reduced for children with contact and flame burns, respectively. Inadequate first aid treatment was also found to be more common for childre

Cytotoxicity testing of silver-containing burn treatments using primary and immortal skin cells

A novel burn wound hydrogel dressing has been previously developed which is composed of 2-acrylamido-2-methylpropane sulfonic acid sodium salt with silver nanoparticles (silver AMPS). This study compared the cytotoxicity of this dressing to the commercially available silver products; Acticoat™, PolyMem Silver® and Flamazine™ cream. Human keratinocytes (HaCaT and primary HEK) and normal human fibroblasts (NHF) were exposed to dressings incubated on Nunc™ polycarbonate inserts for 24, 48 and 72h. Four different cytotoxicity assays were performed including; Trypan Blue cell count, MTT, Celltiter-Blue™ and Toluidine Blue surface area assays. The results were expressed as relative cell viability compared to an untreated control. The cytotoxic effects of Acticoat™ and Flamazine™ cream were dependent on exposure time and cell type. After 24h exposure, Acticoat™ and Flamazine™ cream were toxic to all tested cell lines. Surprisingly, HaCaTs treated with Acticoat™ and Flamazine™ had an improved ability to survive at 48 and 72h while HEKs and NHFs had no improvement in survival with any treatment. The novel silver hydrogel and PolyMem Silver® showed low cytotoxicity to all tested cell lines at every time interval and these results support the possibility of using the novel silver hydrogel as a burn wound dressing. Researchers who rely on HaCaT cells as an accurate keratinocyte model should be aware that they can respond differently to primary skin cells

First aid treatment of burn injuries [editorial]

The recommendations for the first aid treatment of burn injuries have previously been based upon conflicting published studies and as a result the recommendations have been vague with respect to optimal first aid treatment modality, temperature, duration and delay after which treatment is still effective. The public have also continued to use treatments such as ice and alternative therapies, however there is little evidence to support their use. Recently there have been several studies conducted by burn researchers in Australia which have enabled the recommendations to be clarified. First aid should consist of cool running water (2-15°C), applied for 20 minutes duration, as soon as possible but for up to 3 hours after the burn injury has occurred. Ice should not be used and alternative therapies should only be used to relieve pain as an adjunct to cold water treatment. Optimal first aid treatment significantly reduces tissue damage, hastens wound re-epithelialisation and reduces scarring and should be promoted widely to the public

Comparing the reported burn conditions for different severity burns in porcine models: a systematic review

There are many porcine burn models that create burns using different materials (e.g. metal, water) and different burn conditions (e.g. temperature and duration of exposure). This review aims to determine whether a pooled analysis of these studies can provide insight into the burn materials and conditions required to create burns of a specific severity. A systematic review of 42 porcine burn studies describing the depth of burn injury with histological evaluation is presented. Inclusion criteria included thermal burns, burns created with a novel method or material, histological evaluation within 7 days post-burn and method for depth of injury assessment specified. Conditions causing deep dermal scald burns compared to contact burns of equivalent severity were disparate, with lower temperatures and shorter durations reported for scald burns (83°C for 14 seconds) compared to contact burns (111°C for 23 seconds). A valuable archive of the different mechanisms and materials used for porcine burn models is presented to aid design and optimisation of future models. Significantly, this review demonstrates the effect of the mechanism of injury on burn severity and that caution is recommended when burn conditions established by porcine contact burn models are used by regulators to guide scald burn prevention strategies

Cytotoxicity testing of burn wound dressings, ointments and creams : a method using polycarbonate cell culture inserts on a cell culture system

We have developed a method to test the cytotoxicity of wound dressings, ointments, creams and gels used in our Burn Centre, by placing them on a permeable Nunc Polycarbonate cell culture insert, incubated with a monolayer of cells (HaCaTs and primary human keratinocytes). METHODS: We performed two different methods to determine the relative toxicity to cells. (1) Photo visualisation: The dressings or compounds were positioned on the insert's membrane which was placed onto the monolayer tissue culture plate. After 24 h the surviving adherent cells were stained with Toluidine Blue and photos of the plates were taken. The acellular area of non-adherent dead cells which had been washed off with buffer was measured as a percentage of the total area of the plate. (2) Cell count of surviving cells: After 24 h incubation with the test material, the remaining cells were detached with trypsin, spun down and counted in a Haemocytometer with Trypan Blue, which differentiates between live and dead cells. RESULTS: Seventeen products were tested. The least cytotoxic products were Melolite, White soft Paraffin and Chlorsig1% Ointment. Some cytotoxicity was shown with Jelonet, Mepitel((R)), PolyMem((R)), DuoDerm((R)) and Xeroform. The most cytotoxic products included those which contained silver or Chlorhexidine and Paraffin Cream a moisturizer which contains the preservative Chlorocresol. CONCLUSION: This in vitro cell culture insert method allows testing of agents without direct cell contact. It is easy and quick to perform, and should help the clinician to determine the relative cytotoxicity of various dressings and the optimal dressing for each individual wound

Acticoat (TM): A cost-effective and evidence-based dressing strategy

We thank Dr. Burd et al. for taking an interest in our paper [1]. The retrospective cohort study was performed and published for two reasons. Firstly, we wished to compare and contrast the use of Acticoat™ and Silvazine™, and secondly we wished to demonstrate how one's practice can be dramatically altered by a change in dressing used. We found that Acticoat™ was safe and easy to use, caused less trauma to patients, required less frequent dressing changes and enabled treatment to be conducted on an outpatient, rather than an inpatient basis. During the period of Acticoat™ treatment we also saw a dramatic reduction in grafting requirements and also in the need for long-term scar management. Burd et al. correctly state that silver-based dressings are now more widely available, however many burn centres in the world continue to use silver sulphadiazine with daily baths. We therefore feel that a comparison is very relevant and useful. Prospective, randomised clinical trials of a range of silver-based dressings would indeed be useful, and hopefully Dr. Burd and colleagues will take up their own suggestion and perform these studies..

A review of first aid treatments for burn injuries

Throughout history there have been many different and sometimes bizarre treatments prescribed for burns. Unfortunately many of these treatments still persist today, although they often do not have sufficient evidence to support their use. This paper reviews common first aid and pre-hospital treatments for burns (water--cold or warm, ice, oils, powders and natural plant therapies), possible mechanisms whereby they might work and the literature which supports their use. From the published work to date, the current recommendations for the first aid treatment of burn injuries should be to use cold running tap water (between 2 and 15 degrees C) on the burn, not ice or alternative plant therapies

Quantifying the efficacy of first aid treatments for burn injuries using mathematical modelling and in vivo porcine experiments

First aid treatment of burns reduces scarring and improves healing. We quantify the efficacy of first aid treatments using a mathematical model to describe data from a series of in vivo porcine experiments. We study burn injuries that are subject to various first aid treatments. The treatments vary in the temperature and duration. Calibrating the mathematical model to the experimental data provides estimates of the thermal diffusivity, the rate at which thermal energy is lost to the blood, and the heat transfer coefficient controlling the loss of thermal energy at the interface of the fat and muscle. A limitation of working with in vivo experiments is the difficulty of measuring variations in temperature across the tissue layers. This limitation motivates us to use a simple, single layer mathematical model. Using the solution of the calibrated mathematical model we visualise the temperature distribution across the thickness of the tissue. With this information we propose a novel measure of the potential for tissue damage. This measure quantifies two important factors: (i) the volume of tissue that rises above the threshold temperature associated with the accumulation of tissue damage; and (ii) the duration of time that the tissue remains above this threshold temperature