Skin 11ß-hydroxysteroid dehydrogenase type 1 enzyme expression regulates burn wound healing and can be targeted to modify scar characteristics.

Background: Excessive scarring and fibrosis are the most severe and common complications of burn injury. Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin, leading to skin thinning and impaired wound healing. Skin can generate active glucocorticoids locally through expression and activity of the 11ß-hydroxysteroid dehydrogenase type 1 enzyme (11ß-HSD1). We hypothesised that burn injury would induce 11ß-HSD1 expression and local glucocorticoid metabolism, which would have important impacts on wound healing, fibrosis and scarring. We additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn scarring. Methods: Skin 11ß-HSD1 expression in burns patients and mice was examined. The impacts of 11ß-HSD1 mediating glucocorticoid metabolism on burn wound healing, scar formation and scar elasticity and quality were additionally examined using a murine 11ß-HSD1 genetic knockout model. Slow-release scaffolds containing therapeutic agents, including active and inactive glucocorticoids, were developed and pre-clinically tested in mice with burn injury. Results: We demonstrate that 11ß-HSD1 expression levels increased substantially in both human and mouse skin after burn injury. 11ß-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition, tensile strength and stiffness, features characteristic of excessive scarring. Application of slow-release prednisone, an inactive glucocorticoid, slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation, myofibroblast generation, collagen production and scar stiffness. Conclusions: Skin 11ß-HSD1 expression is a key regulator of wound healing and scarring after burn injury. Application of an inactive glucocorticoid capable of activation by local 11ß-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics post burn injury.

Cold burns as a result of cosmetic cryolipolysis: An emerging concern from the NSW Statewide Burn Injury Service.

Cold burns are an uncommon mechanism of burn injury in Australia, where environmental exposure to freezing temperatures is rare. Aetiological research shows that most likely causes are related to intentional injury or industrial accidents1 Cryolipolysis, a cosmetic technique advertised as 'fat freezing', has recently emerged as a method of fat reduction and body contouring. Whilst perceived as safe4,5, this study presents the world's first case series on cold burns sustained from cryolipolysis. A retrospective review was undertaken of the New South Wales Statewide Burn Injury Service (SBIS) Registry, a prospectively collected database of all patients treated by NSW burns units. Ten patients from 2012 to 2020 were identified who sustained cold burns as a direct complication of cosmetic cryolipolysis. Mean total body surface area (TBSA) injured was 1% (range 0.5-3%). Burn depth ranged from superficial to full thickness. Two patients required excision and split-thickness skin grafts. Mean time to complete healing was 10 days (range 7-13) for those patients with partial thickness injuries, and 38 days (range 32-45) for those who required skin grafts. This case series provides strong evidence that cyrolipolysis can cause cold burns leading to varying degrees of skin injury, even requiring skin grafts. These injuries should be classified as burns and referred to specialist burn centres for treatment. Further research is needed to determine the specific aspects of cryolipolysis cold burn risk, and practitioners trained to reduce this risk and include it in consent processes. The authors advocate for education and regulation to prevent such injuries, and challenge perceptions of the technique as a minor, risk-free cosmetic treatment.

Alginate Dressings Continuously for 14 Days on Uncontaminated, Superficial, Partial Thickness Burns.

Calcium alginate dressings are commonly used on split-thickness skin donor sites, where they are typically removed after 14 days. Alginates have been used previously on superficial, partial thickness burns, but changed every 3 to 5 days. In this study, alginates were applied to superficial, partial thickness burns on adults within 36 hours of injury, then left intact for up to 14 days. Wound healing (≥95% wound epithelialization) and pain were measured. Twenty-one burns were reviewed on ten patients. Per the initial protocol, six patients were reviewed every 3 to 5 days, with removal of only secondary dressings, until days 13 to 14, when the alginate dressings were removed. One patient was reviewed every 3 to 5 days until day 10, when a clinic nurse removed the alginate dressing. Restrictions on movement during the COVID pandemic necessitated a protocol change, with only one review at approximately day 14 for removal of alginate and secondary dressings; three patients were reviewed in this manner. Burns on all patients were 100% epithelialized at the time of final review and there were no complications, such as scarring, infection, or need for grafting. Following initial debridement and dressings, patients reported minimal pain. Dressing costs appeared to be significantly decreased. This protocol may be particularly useful for patients managed in rural and remote locations, with telemedicine support if required.

Challenges and innovations in treating chronic and acute wound infections: from basic science to clinical practice.

Acute and chronic wound infection has become a major worldwide healthcare burden leading to significantly high morbidity and mortality. The underlying mechanism of infections has been widely investigated by scientist, while standard wound management is routinely been used in general practice. However, strategies for the diagnosis and treatment of wound infections remain a great challenge due to the occurrence of biofilm colonization, delayed healing and drug resistance. In the present review, we summarize the common microorganisms found in acute and chronic wound infections and discuss the challenges from the aspects of clinical diagnosis, non-surgical methods and surgical methods. Moreover, we highlight emerging innovations in the development of antimicrobial peptides, phages, controlled drug delivery, wound dressing materials and herbal medicine, and find that sensitive diagnostics, combined treatment and skin microbiome regulation could be future directions in the treatment of wound infection.

Controlled dual release of dihydrotestosterone and flutamide from polycaprolactone electrospun scaffolds accelerate burn wound healing.

Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti-androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti-androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full-thickness burn wound healing, mouse model, DHT/F-scaffold showed a significantly faster wound healing compared with F-scaffold or DHT-scaffold. Histology analysis confirmed that DHT/F-scaffold exhibited higher re-epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen-dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients.

Wound healing and dermal regeneration in severe burn patients treated with NovoSorb® Biodegradable Temporising Matrix: A prospective clinical study.

INTRODUCTION: For extensive burns, autologous donor skin may be insufficient for early debridement and grafting in a single stage. A novel, synthetic polyurethane dermal template (NovoSorb® Biodegradable Temporising Matrix, BTM) was developed to address this need. The aim of this study was to evaluate use of BTM for primary dermal repair after deep burn injury. METHODS: A multicentre, prospective, clinical study was conducted from September 2015 to May 2018. The primary endpoint was % split skin graft take over applied BTM at 7-10 days after grafting. Secondary endpoints included % BTM take, incidence of infection and adverse events, and scar quality to 12 months after BTM application. RESULTS: Thirty patients were treated with BTM and delayed split skin grafting. The % graft take had a mean of 81.9% and % BTM take had a mean of 88.6%, demonstrating effective integration of BTM. When managed appropriately, it was possible for BTM to integrate successfully despite findings suggestive of infection. Scar quality improved over time. DISCUSSION: These results provide additional clinical evidence on the safety and performance of BTM as an effective dermal substitute in the treatment of patients with deep burn injuries.

Low-protein diet accelerates wound healing in mice post-acute injury.

BACKGROUND: Wound healing processes are influenced by macronutrient intake (protein, carbohydrate and fat). The most favourable diet for cutaneous wound healing is not known, although high-protein diets are currently favoured clinically. This experimental study investigates the optimal macronutrient balance for cutaneous wound healing using a mouse model and the Geometric Framework, a nutrient modelling method, capable of analyzing the individual and interactive effects of a wide spectrum of macronutrient intake. METHODS: Two adjacent and identical full-thickness skin excisions (1 cm2) were surgically created on the dorsal area of male C57BL/6 mice. Mice were then allocated to one of 12 high-energy diets that varied in protein, carbohydrate and fat content. In select diets, wound healing processes, cytokine expression, energy expenditure, body composition, muscle and fat reserves were assessed. RESULTS: Using the Geometric Framework, we show that a low-protein intake, coupled with a balanced intake of carbohydrate and fat is optimal for wound healing. Mice fed a low-protein diet progressed quickly through wound healing stages with favourable wound inflammatory cytokine expression and significantly accelerated collagen production. These local processes were associated with an increased early systemic inflammatory response and a higher overall energy expenditure, related to metabolic changes occurring in key macronutrient reserves in lean body mass and fat depots. CONCLUSIONS: The results suggest that a low-protein diet may have a greater potential to accelerate wound healing than the current clinically used high-protein diets.

The contradictory role of androgens in cutaneous and major burn wound healing.

Wound healing is a complex process involving four overlapping phases: haemostasis, inflammation, cell recruitment and matrix remodeling. In mouse models, surgical, pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-α production and reduce wound re-epithelization and matrix deposition, retarding cutaneous wound healing. Similarly, clinical studies have shown that cutaneous wound healing is slower in men compared to women. However, in major burn injury, which triggers not only local wound-healing processes but also systemic hypermetabolism, the role of androgens is poorly understood. Recent studies have claimed that a synthetic androgen, oxandrolone, increases protein synthesis, improves lean body mass and shortens length of hospital stay. However, the possible mechanisms by which oxandrolone regulates major burn injury have not been reported. In this review, we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing, as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.

Foot burns: A comparative analysis of diabetic and non-diabetic patients.

INTRODUCTION: Foot burns represent a small part of the body with many challenges. The impact of diabetes on clinical outcomes adds further issues in management that clinicians must consider in their management. These factors have serious implications on morbidity and long term sequelae. Our aim is to analyse epidemiological trends of foot burns and examine the differences between diabetic and non-diabetics at Concord hospital from 2014 to 2019. METHODS: A retrospective audit from 2014-19 at Concord General Repatriation Hospital Burns Unit summarised patient demographics, burn injury, diabetic status, operations and length of stay. All foot burn injuries from 2014-19 of all ages and gender that attended Concord burns hospital were included in this study. RESULTS: We treated 797 patients who presented with foot burns, of which 16.2% were diabetic. The average age was higher in diabetics (60.72 years) than non-diabetics (39.72 years) and more males suffered burns compared to females in both groups (p < 0.001). There was a larger portion of elderly patients (greater than 65 years old, 15.1% of total) who sustained foot burns in the diabetic group compared to the non-diabetic group (p < 0.001). The most affected season was summer (27.0%), but diabetic patients were 1.7 times more likely to sustain injury in winter than non-diabetics. Diabetics were 3.8 times more likely to have contact burns compared to non-diabetic patients (p < 0.001). In a multivariable linear regression analysis, factors that contributed to increased length of stay included elderly status, place of event, diabetic status, number of operations, ICU admission, wound infection, amputation, and admission [F (16, 757 = 41.149, p < 0.001, R2 = 0.465]. CONCLUSIONS: With the increase of diabetes, our multidisciplinary approach to diabetic foot care should include nursing, medical and surgical disciplines to identify patients at risk. The data highlights that a focus on prevention and education for diabetes is central to optimize glycaemic control and burn management, whilst providing a multidisciplinary network on discharge.

Treatment of Partial Thickness Burns: A Prospective, Randomized Controlled Trial Comparing Four Routinely Used Burns Dressings in an Ambulatory Care Setting.

This prospective, randomized controlled trial study compared the effects of four dressings for adult partial thickness burns, focusing on re-epithelialization time and cost effectiveness. Adults with partial thickness burns meeting inclusion criteria were randomized to either Biobrane™, Acticoat™, Mepilex® Ag, or Aquacel® Ag. Primary endpoint for analysis was >95% re-epithelialization. Incremental cost-effectiveness ratios were calculated based on dressing costs. Dominance probabilities between treatment arms were calculated from bootstrap resampling trial data. One hunderd thirty-one partial thickness burn wounds in 119 patients were randomized. Adjusting for sex, age, smoking status, burn mechanism, TBSA, and first aid adequacy, Mepilex® Ag had a reduced time to re-epithelialization compared to Biobrane™ (IRR: 1.26; 95% CI: 1.07-1.48, P < .01). Economic analysis showed that there was a 99%, 71%, and 53% probability that Mepilex® Ag dominated (cheaper and more effective) Biobrane™, Acticoat™, and Aquacel® Ag, respectively. Mepilex® Ag achieved faster re-epithelialization and better cost effectiveness. Patient satisfaction and comfort seems better with Biobrane™ although not reflected within the end outcome of the healed wound. It is the patients' (after extensive education) and clinicians' choice, level of experience, and availability of products in praxis that will guide the decision as to which the product is used individually on which patient.

Effectiveness and safety of ablative fractional CO2 laser for the treatment of burn scars: A case-control study.

BACKGROUND: Burn scars are a major clinical challenge. The aim of this study was to determine the effectiveness and safety of one treatment with the ablative fractional CO2 laser (AFL-CO2) compared to standard burn scar treatment. METHOD: From December 2014 to October 2018 patients were prospectively recruited and treatment effects analyzed by assessing various outcome parameters from the date of first consultation and after treatment. A case control study was conducted looking at the impact of one AFL-CO2 treatment compared to a cohort subjected to conventional conservative treatment. Adverse effects were noted at follow up. RESULTS: 187 patients were included, with 167 in the AFL-CO2, and 20 in the control cohort. Baseline demographics and scar characteristics showed no significant differences. Ultrasound measured scar thickness as well as the Vancouver Scar Scale (VSS) revealed a significant reduction in the treatment cohort, but no significant improvement in the control group. The POSAS-O was significantly improved in both cohorts. Subjective parameters (POSAS-P, DN4-Pain, and modified D4Pruritus scores) decreased significantly in the AFL-CO2 cohort but remained unchanged in the control group. The BSHS-B quality of life score increased significantly in the AFL-CO2 group, but worsened at the follow up of the untreated patients. Sub-domain analyses found the biggest differences in Affect, Body Image, Heat Sensitivity, Treatment and Work. Complications occurred in 5 patients (2.9%). CONCLUSIONS: This study demonstrates that AFL-CO2 is an effective and safe treatment modality for burn scars improving thickness, symptoms and quality of life of burn survivors when compared to conventional scar treatment.

Dihydrotestosterone (DHT) Enhances Wound Healing of Major Burn Injury by Accelerating Resolution of Inflammation in Mice.

Androgens have been known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. The aim of this study is to investigate the role of dihydrotestosterone (DHT) as a new therapeutic approach in treating major burn injury. In the present study, mice received systemic androgen treatment post major burn injury. Wound healing rate and body weight were monitored over 21 days. The serum level of inflammatory cytokines/chemokines were measured using multiplex immunoassays. In addition, splenocyte enumeration was performed by flow cytometry. Healing phases of inflammation, re-epithelialization, cell proliferation and collagen deposition were also examined. In results, DHT treated mice lost less weight and displayed accelerated wound healing but has no impact on hypermetabolism. Mice, after burn injury, displayed acute systemic inflammatory responses over 21 days. DHT treatment shortened the systemic inflammatory response with reduced splenic weight and monocyte numbers on day 14 and 21. DHT treatment also reduced wound infiltrating macrophage numbers. In conclusion, DHT treatment facilitates local wound healing by accelerating the resolution of inflammation, but not through alterations of post-burn hypermetabolic response.

Geometric framework reveals that a moderate protein, high carbohydrate intake is optimal for severe burn injury in mice.

Nutritional therapy is a cornerstone of burns management. The optimal macronutrient intake for wound healing after burn injury has not been identified, although high-energy, high-protein diets are favoured. The present study aimed to identify the optimal macronutrient intake for burn wound healing. The geometric framework (GF) was used to analyse wound healing after a 10 % total body surface area contact burn in mice ad libitum fed one of the eleven high-energy diets, varying in macronutrient composition with protein (P5-60 %), carbohydrate (C20-75 %) and fat (F20-75 %). In the GF study, the optimal ratio for wound healing was identified as a moderate-protein, high-carbohydrate diet with a protein:carbohydrate:fat (P:C:F) ratio of 1:4:2. High carbohydrate intake was associated with lower mortality, improved body weight and a beneficial pattern of body fat reserves. Protein intake was essential to prevent weight loss and mortality, but a protein intake target of about 7 kJ/d (about 15 % of energy intake) was identified, above which no further benefit was gained. High protein intake was associated with delayed wound healing and increased liver and spleen weight. As the GF study demonstrated that an initial very high protein intake prevented mortality, a very high-protein, moderate-carbohydrate diet (P40:C42:F18) was specifically designed. The dynamic diet study was also designed to combine and validate the benefits of an initial very high protein intake for mortality, and subsequent moderate protein, high carbohydrate intake for optimal wound healing. The dynamic feeding experiment showed switching from an initial very high-protein diet to the optimal moderate-protein, high-carbohydrate diet accelerated wound healing whilst preventing mortality and liver enlargement.

Ablative fractional resurfacing with laser-facilitated steroid delivery for burn scar management: Does the depth of laser penetration matter?

BACKGROUND AND OBJECTIVE: To investigate whether the depth of ablative fractional CO2 laser (CO2 -AFL) penetration of pathological burn scars influences clinical outcomes. STUDY DESIGN/MATERIALS AND METHODS: All patients presenting to the Concord Repatriation General Hospital (CRGH) Scar Clinic received ultrasound measurement at the thickest point of their burn scars. Subsequently, the effect of various CO2 -AFL settings (energy which correlates to penetration depths) on different outcome parameters was analysed. Patients were divided into five groups depending on minimal scar penetration depth. RESULTS: Seventy-eight patients (158 scars) had complete data allowing for analysis. Median scar thickness was 3,400 µm and median laser scar penetration depth was 900 µm. Scar penetration categories were as follows: 0-25% (n = 40), 25-50% (n = 67), 50-75% (n = 31), 75-100% (n = 8), >100% (n = 3) of scar thickness. The median reduction in maximum scar thickness was 800 µm following one treatment (P < 0.001). However, this effect depended on scar penetration depth, whereby scars that were penetrated ≥75% showed no significant improvement in scar thickness and those penetrated >100% indicated a tendency to become worse. Other assessed outcome parameters included: the Vancouver Scar Scale, the Patient and Observer Scar Assessment Scale, a neuropathic pain score (DN4 Pain Questionnaire), and a pruritus score (modified D4 Pruritus Score). All these factors showed significant improvement in the categories up to 75% scar penetration depth. CONCLUSIONS: CO2 -AFL scar penetration depth significantly influences subjective and objective pathologic burn scar modulation. The penetration depth of 51-75% achieves the greatest reduction in scar thickness. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Mouse models in burns research: Characterisation of the hypermetabolic response to burn injury.

OBJECTIVE: The aim of the study is to characterise burn induced hypermetabolism in a mouse model. SUMMARY BACKGROUND DATA: There are many mouse models of burn injury currently available however, their use in burns research is limited by the general assumption that post-burn hypermetabolism is difficult to study in these models. METHODS: Male Balb/c mice were subjected to either a small (1 cm2) or large (4 cm2) contact burn. The hypermetabolic response to burn injury was determined by measuring changes in basal energy expenditure. The hormonal and inflammatory mediators of hypermetabolism, and the catabolic alterations secondary to hypermetabolism were also examined. RESULTS: Post-burn hypermetabolism was induced in both models of small and large burn. However, large burns resulted in prolonged wound healing, a more pronounced and sustained increase in basal energy expenditure, and a greater stress and systemic inflammatory response with profound catabolic consequences. CONCLUSIONS: In the present study, we have successfully characterised the burn induced systemic hypermetabolic response in a mouse model of small and large burn. These models may prove useful for researchers studying the complex aetiology of hypermetabolism and interventions.

Ablative fractional resurfacing for burn scar management affects the number and type of elective surgical reconstructive procedures, hospital admission patterns as well as length of stay.

BACKGROUND: Reconstructive surgery remains the main approach to address burn scar contractures. Ablative fractional resurfacing is an increasingly popular tool for severe burn scar management, but its effect on overall burns reconstructive case-mix, operating time and patterns of hospital admission have not been reported. METHODS: Retrospective analysis of hospital administrative data from September 2013 to June 2017 was performed evaluating these effects of ablative fractional CO2 laser (CO2-AFL). RESULTS: The total number of acute burn patients treated at CRGH increased substantially over this timeframe, resulting in 412 elective procedures including 82 before and 330 after introducing CO2-AFL. The proportion of traditional non-laser reconstructive procedures dropped considerably to 23.9% in about 2.5 years following CO2-AFL introduction. This change in approach had a profound effect on LOS with average LOS being 1.96days for non-laser and 0.36days for CO2-AFL-procedures (p<0.001). Anaesthetic times also decreased significantly, with median durations at 90min pre-laser and 64min post-laser introduction (p<0.001), and median anaesthetic times at 87min (non-AFL) and 57min (AFL procedures) (p<0.001). CONCLUSION: AFL profoundly affects elective reconstructive burn case mix with a replacement of conventional reconstructive operations in favour of AFL-procedures. This results in reductions of average LOS and anaesthetic times. Consequently, increased use of AFL in burn scar management could potentially reduce overall costs associated with burn scar reconstruction.

First aid is associated with improved outcomes in large body surface area burns.

BACKGROUND: Animal studies indicate treating burn injuries with running water (first aid) for 20 min up to 3 h after burn reduces healing time and scarring. We have previously demonstrated the benefits of first aid in minor burn injuries with respect to a reduction in wound depth, faster healing, and decreased skin grafting utilisation. The purpose of this cohort study was to assess the effect of first aid on clinical outcomes in large body surface area burn injuries (≥20%). METHODS: Data was prospectively collected for patients with ≥20% TBSA burns from 2004- 2018. Multivariate regression analysis was used to determine the association of adequate first aid with 8 outcomes - mortality, total length of stay, total body surface area (TBSA), percentage/proportion of TBSA that was full thickness [PFTI], TBSA grafted, number of re-grafting sessions, intensive care admission, and intensive care length of stay. Adequate first aid was defined as the application of 20 min of cool, running tap water up to 3 h following the burn injury. FINDINGS: 390 patients were identified. Adequate first aid was received in 35.6% (139) of patients. There was a trend towards a reduction in mortality (OR 0.37; 95% CI 0.12-1.13; P = 0.08). Patients who received adequate first aid had a statistically significant 9.8% reduction in TBSA (95% CI -13.6% to -6.1%; P < 0.0001) as well as a 12% lower PTFI compared to patients who received inadequate first aid (95% CI -19% to -4%; P < 0.01). Whilst there was no significant effect of adequate first aid on the TBSA grafted (P = 0.37), adequate first aid was associated with a significantly less number of re-grafting sessions (95% CI --0.29 to -0.08; P < 0.001). INTERPRETATION: Adequate first aid with 20 min of running water is associated with improved outcomes in large burn injuries. Significant benefits are seen in a reduction in TBSA, proportion of the burn wound that is full thickness, as well as decreased re-grafting. This has significant patient and health system benefits and adds to the body of evidence supporting 20 min of cooling in burns care.