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Abnormal fibrinolysis early after injury has been associated with increased mortality in trauma patients, but no studies have addressed patients with burn injury. This prospective cohort study aimed to characterize fibrinolytic phenotypes in burn patients and to see if they were associated with mortality. Patients presenting to a regional burn centre within 4 h of thermal injury were included. Blood was collected for sequential viscoelastic measurements using thromboelastography (RapidTEG™) over 12 h. The percentage decrease in clot strength 30 min after the time of maximal clot strength (LY30) was used to categorize patients into hypofibrinolytic/fibrinolytic shutdown (SD), physiological (PHYS) and hyperfibrinolytic (HF) phenotypes. Injury characteristics, demographics and outcomes were compared. Of 115 included patients, just over two thirds were male. Overall median age was 40 (i.q.r. 28-57) years and median total body surface area (TBSA) burn was 13 (i.q.r. 6-30) per cent. Some 42 (36.5 per cent) patients had severe burns affecting over 20 per cent TBSA. Overall mortality was 18.3 per cent. At admission 60.0 per cent were PHYS, 30.4 per cent were SD and 9.6 per cent HF. HF was associated with increased risk of mortality on admission (odds ratio 12.61 (95 per cent c.i. 1.12 to 142.57); P = 0.041) but not later during the admission when its incidence also decreased. Admission SD was not associated with mortality, but incidence increased and by 4 h and beyond, SD was associated with increased mortality, compared with PHYS (odds ratio 8.27 (95 per cent c.i. 1.16 to 58.95); P = 0.034). Early abnormal fibrinolytic function is associated with mortality in burn patients.

Fasciotomy is a limb-saving procedure in the management of ischemic extremities. Little evidence exists as to the best method of fasciotomy wound management. We hypothesized that the use of vacuum dressing (VAC) or creation of dynamic tension (DYN) would increase rates of primary closure, reducing the need for split thickness skin grafting (STSG). The records of a large urban Level I trauma center were used to identify fasciotomy recipients over a 10-year period and were retrospectively analyzed. Data collected included injury characteristics, wound management, and outcomes. Wound management was dictated by surgeon preference, and categorized as gauze packing, DYN, or VAC. The primary outcome was primary closure versus need for STSG. Wound management cohorts were compared using logistic regression. Fisher's exact test and χ(2) were performed to compare proportions and categorical variables respectively. From 2000 to 2009, 227 patients had a fasciotomy performed. Mechanism, age, and incidence of fracture were different between the groups. There was a trend towards increased primary closure with DYN (83%). Average length of stay (LOS) was 21 days for those receiving primary closure and 27 days for STSG. There was a significant decrease in LOS for the DYN group (average 16 days) when compared with gauze packing and VAC. In this series of 227 patients who underwent fasciotomy, no technique of wound management produced a significant improvement in primary closure rate. A trend toward more primary closure was seen in the DYN group. LOS was longer for patients receiving STSG. The DYN cohort had a significantly shorter LOS. [ABSTRACT FROM AUTHOR]

Introduction: Plasma inclusive resuscitation (PIR) uses fresh frozen plasma as an adjunct to crystalloid in the management of burn shock and has potential benefits over other colloids. Yet, safety concerns for transfusion-related acute lung injury (TRALI) exist. The aim of this study evaluated the association between TRALI and PIR in a cohort of severely burn-injured patients using the updated Canadian Blood Services Consensus definitions., Methods: Burn-injured patients requiring PIR at a burn center from 2018 to 2022 were retrospectively reviewed. To assess for TRALI, data related to acute hypoxemia, bilateral pulmonary edema, left atrial hypertension, and changes to respiratory status up to 6 h after PIR were recorded. To identify other risks and benefits associated with PIR timing, resuscitative volumes and outcomes were compared between early (0-8 h) and late PIR (8-24 h) initiation., Results: Of the 88 patients included for study, no patient developed TRALI type I or II under the updated definitions. Early (n = 39) compared to late PIR (n = 49) was associated with a higher percent total body surface area (TBSA, 36.3%, 26.0%, P = 0.01). The predicted 24-h volume was higher for early PIR (10.1 L, 6.3 L, P = 0.049), but the observed 24-h volume (cc/kg/%TBSA) was not significantly different (5.2, 5.3, P = 0.62)., Conclusions: In a cohort of severely burn-injured patients undergoing PIR, no patient developed TRALI type I or type II under the updated Canadian Blood Services Consensus definitions. Earlier use of PIR was not associated with higher resuscitative volumes despite higher TBSA. Further studies are necessary to better ascertain the potential risks and benefits associated with PIR., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The contribution of endothelial injury to the pathogenesis of burn shock is not well characterized. This work investigates potential mechanisms underlying dysregulation of endothelial barrier function by burn patient plasmas., Methods: Plasma was collected from burn-injured patients (n = 8) within 4 h of admission. Demographic and injury characteristics were collected and markers of injury severity including international normalized ratio, activated partial thromboplastin time, and levels of syndecan-1 and interleukin (IL)-6, IL-1B, IL-10, Il-12p70, and tumor necrosis factor-α measured. Human umbilical vein endothelial cell monolayers (HUVEC-m) exposed to either burn patient plasma or multidonor plasma (HHP) were assessed for permeability (40 kDa fluorescein isothiocyanate (FITC)-Dextran diffusion), intercellular gap area (F-actin staining) and incidence of apoptosis (TUNEL assay). Post plasma exposure, RNA was isolated and used in polymerase chain reaction (PCR) arrays targeting genes relevant to cytoskeletal structure or apoptosis. Differences between HHP and burn plasma-treated HUVEC-m were analyzed., Results: Five plasmas promoted significant increases in HUVEC-m permeability. When plasmas were grouped based on their capacity to increase permeability, no differences in age, %total body surface area, gender, hospital mortality, international normalized ratio, activated partial thromboplastin time, or cytokine concentration were observed; however, significantly higher syndecan-1 levels were seen in the plasmas inducing increased permeability. Increases in intercellular gap area and apoptosis and relevant gene expression were observed after exposure to patient plasmas but none of these metrics correlated completely with the pattern or magnitude of the changes in permeability., Conclusions: Burn patient plasmas variably disrupt HUVEC-m homeostasis, differentially inducing changes in permeability, intercellular gap area, and apoptosis. Neither increases in intercellular gap size nor apoptosis appear sufficient to explain the pattern of changes in permeability., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A phase 3b, open-label, multicenter, expanded-access study (NCT04123548) evaluated safety and clinical outcomes of StrataGraft treatment in adults with deep partial-thickness thermal burns with intact dermal elements., Methods: Adult patients with 3 % to < 50 % total body surface area burns were treated with a single application of ≤ 1:1 meshed StrataGraft and followed for 24 weeks. Primary endpoint was count and percentage of patients with treatment-emergent adverse events (TEAEs). Secondary endpoints included confirmed wound closure (WC) at Week 12, durable WC at Week 24, time to WC, scar evaluation, and wound infection-related events., Results: Fifty-two patients with 96 treatment sites were enrolled. Pruritus was the most common TEAE (22 patients [42.3 %]). Twenty serious TEAEs occurred in 10 patients (19.2 %); none were related to StrataGraft. There were 4 (7.7 %) deaths (aspiration, myocardial infarction, self-injury, Gram-negative rod sepsis); none were related to StrataGraft. Confirmed WC was achieved by Week 12 in 33 patients (63.5 %; 95 % CI: 50.4-76.5 %) and 69 treatment sites (71.9 %; 95 % CI: 62.9-80.9 %). Durable WC was achieved by Week 24 in 29 patients (55.8 %; 95 % CI: 42.3-69.3 %) and 58 treatment sites (60.4 %; 95 % CI: 50.6-70.2 %)., Conclusions: StrataGraft demonstrated clinical benefit. Safety data were consistent with previously reported findings., Competing Interests: Declaration of Competing Interest James H. Holmes IV: Equity positions in Abbott Labs, AbbVie, Change Healthcare Inc, and Imbed Biosciences. Consultant for Avita Medical and has received research support from Avita Medical, Mallinckrodt Pharmaceuticals/Stratatech, SpectralMD, and Keranetics. Jeffrey W. Shupp: Research funding from Mallinckrodt Pharmaceuticals, Avita Medical, Urgo Medical, ACell, and Kerecis. JWS has been a consultant for Integra LifeSciences and Avita Medical. Tracee Short: Participated in the clinical advisory boards for Avita Medical, Mallinckrodt Pharmaceuticals, Synergy Biologics, Polynovo, and KCI. Victor C. Joe: Participated in a Mallinckrodt Pharmaceuticals Advisory Board relating to StrataGraft. Jeffrey Litt: Participated in the speaker bureau for Acelity/3AM (ended) and advisory board for Vericel (ended). Joshua Carson: Received research funding from Mallinckrodt Pharmaceuticals and the Biomedical Research and Development Authority (BARDA) and personal fees from Integra LifeSciences, Avita Medical, and Mallinckrodt Pharmaceuticals. Jeffrey E. Carter: Equity positions in PermeaDerm, Inc and is a consultant for Avita Medical. Research support from Avita Medical, SpectralMD, and Keranetics. Lucy Wibbenmeyer: Received research funding from Mallinckrodt Pharmaceuticals, Mediwound, and Biomedical Research and Development Authority (BARDA) and consultant fees from Vericel, Allosource, and Mallinckrodt Pharmaceuticals. Helen Hahn: Previous employee of Mallinckrodt Pharmaceuticals. Janice M. Smiell: Previous employee of Mallinckrodt Pharmaceuticals. Randi Rutan: Previous employee of Mallinckrodt Pharmaceuticals. Richard Wu: Employee of Mallinckrodt Pharmaceuticals. Angela L. F. Gibson: Received grant/research support from Mallinckrodt Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Dynamically titrated crystalloids are the standard of care for burn shock resuscitation. There are theoretical concerns that the adjunctive use of allogeneic plasma may perturb the patient's coagulation and inflammation status deleteriously. It was hypothesized that plasma-inclusive resuscitation (PIR) would not be associated with prothrombotic changes relative to baseline after thermal injury., Methods: Patients admitted to a regional burn center who were treated with PIR as part of their burn resuscitation were enrolled. Whole blood samples were analyzed prospectively via rapid thromboelastography and rotational thromboelastometry to assess for coagulopathy at four time points throughout their acute burn resuscitation. The mixed-effect model for repeated measures followed by Tukey's post hoc test for comparisons was used to examine group differences., Results: There were 35 patients in the analysis. Most were male (74.3%) with a median age of 43 y (32-55), concomitant inhalation injury of 28.6%, total body surface area burn size of 34% (27%-48.5%), and the overall mortality of the cohort was 28.6%. There were no transfusion reactions or thrombotic events. There were no differences in thromboelastography or rotational thromboelastometry parameters overall or when stratified by mortality, total body surface area burn, and inhalation injury. There were no significant differences between the fibrinolytic phenotypes over time., Conclusions: Data suggest that PIR was not associated with prothrombotic or lytic changes in burn patients relative to baseline. Further research is needed to confirm these findings and evaluate efficacy of PIR in acute burn resuscitation., (Published by Elsevier Inc.)

Introduction: A common treatment for large deep-to-full-thickness burns is excision and grafting with a widely meshed split-thickness skin graft (mSTSG). Due to the differential healing of the interstices and adhered split-thickness skin graft, wound patterning and delayed wound healing are common outcomes of this treatment. Delayed healing may increase infection rates and wound care requirements, while wound patterning may be psychologically and aesthetically consequential for patients. Autologous skin cell suspension (ASCS) can be used to "over spray" a meshed autograft. It was hypothesized that the use of ASCS combined with mSTSG would increase the rate of wound healing and decrease patterning in healed burn wounds., Methods: Full-thickness burns or excisional wounds (n = 8 each) were created in red Duroc pigs and received 4:1 mSTSGs after wound bed preparation. Half of the wounds received ASCS and half did not at the time of grafting. Percent re-epithelialization, patterning, rete ridge ratio, cellularity, dermal and epidermal thickness, immunofluorescent S100β staining, and melanin index were assessed for each scar., Results: Wounds that received ASCS exhibited increased rates of re-epithelialization (burn +ACSC versus burn-ASCS; day 3 (53.9 ± 3.1 versus 34.3 ± 3.3, P = 0.009): day 5 (68.1 ± 1.6 versus 40.8 ± 3.2, P < 0.001)). Excision +ASCS versus excision-ASCS; day 7 (98.1 ± 1.2 versus 86.4 ± 2.0, day 7 P = 0.022) compared to wounds not treated with ASCS. There was no difference in rete ridge ratio, cellularity, dermal thickness, epidermal thickness, S100β staining, melanin index, or patterning was measured between wounds that received ASCS and those that did not., Conclusions: The addition of ASCS to 4:1 mSTSGs leads to increased rate of wound healing but does not impact the degree of patterning in this model, suggesting that ASCS application likely robustly transfers keratinocytes but not functioning melanocytes at acute timepoints., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Endothelial dysfunction has been implicated in the pathogenesis of burn shock affecting patients with large thermal injury. In response to injury, glycocalyx components like Syndecan-1 (SDC-1) are shed into circulation and have been used as markers of endothelial damage. Previous work in our laboratory has shown that plasma inclusive resuscitation (PIR) with fresh frozen plasma (FFP) ameliorates endothelial damage. However, there remains a paucity of information regarding optimal timing and dosing of PIR as well as organ-specific endothelial responses to shock. We aimed to examine the impact of PIR on endothelial dysfunction using clinically translatable timing and dosing., Methods: Sprague-Dawley rats were used to create thermal burns. Rats were subjected to 40% total body surface area scald burns and were resuscitated with lactated Ringer's (LR) only, LR plus albumin, and LR plus early 1 mL boluses of FFP at 0, 2, 4, and 8 hours postinjury. A late group also received LR plus FFP starting at hour 10 postinjury. Syndecan-1 levels were quantified by enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction analysis characterized transcription of glycocalyx components and inflammatory cytokines in the lung and spleen. Evan's blue dye was used to quantify amount of vascular leakage., Results: Lactated Ringer's plus early FFP reduced Evan's blue dye extravasation when compared with LR only groups, while late FFP did not. When comparing LR only versus LR plus early FFP, SDC-1 levels were reduced in the LR plus early FFP group at hours 8, 12, and 24 (5.23 vs. 2.07, p < 0.001; 4.49 vs. 2.05, p < 0.01; and 3.82 vs. 2.08, p < 0.05, respectively). Lactated Ringer's only groups had upregulation of Exostosin-1 and SDC-1 in the lung compared with LR plus early FFP groups ( p < 0.01 and p < 0.05) and upregulation of cytokines interluekin-10 and interferon γ ( p < 0.001 and p < 0.001)., Conclusion: Early administration of LR plus FFP reduces the magnitude of SDC-1 shedding and dampens the cytokine response to injury. The upregulation of glycocalyx components as a response to endothelial injury is also decreased in the lung and spleen by LR plus early FFP administration., (Copyright © 2024 American Association for the Surgery of Trauma.)

Introduction: Literature examining the impact of obesity on burn injury remains mixed. Previous examination of the National Burn Repository, now the BCQP, in obesity-related burn research is limited. The aim of this work was to provide an assessment of the BCQP dataset to examine the effect of obesity on burn-related outcomes., Materials and Methods: A retrospective review of the BCQP dataset from 2015-2018 was conducted. The primary outcome measure was mortality. Secondary outcomes included overall length of stay (LOS), ICU LOS, and total hospital costs. Patients were grouped as obese or non-obese and were further stratified by total body surface area burned (TBSA) for comparison purposes. Multiple logistic regression (MLG) was used to compare the effect of several independent variables on mortality, ICU LOS > 7days, hospital LOS > 10 days, and total hospital costs > $200,000., Results: Of 41,031 patients in the analysis, 3845 (9.37 %) were obese. Obese patients had a higher mean TBSA (p = 0.01), longer overall LOS (p < 0.001), ICU LOS (p < 0.001), and total hospital costs (p < 0.001). MLG found obesity to be an independent predictor of ICU LOS > 7 days, hospital LOS > 10 days, and total hospital costs > $200,000. Obesity was not an independent predictor of mortality in burn patients, even when stratified by burn size., Conclusions: The presence of obesity in this dataset was not found to be a predictor of mortality for any burn size, but was a predictor of overall LOS, ICU LOS, and total hospital costs. Including obesity-related variables in databases may improve analysis in obesity-related burn research., Competing Interests: Declaration of Competing Interest The authors have no financial or personal relationships with other people or organizations to report that could inappropriately influence this work. The authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Recognition of invasive burn wound sepsis as a major cause of morbidity and mortality in burn injured patients has profoundly changed the management of burn wounds and its associated complications. The development of effective topical antimicrobial therapy is one of the last major developments of modern burn care and has been driven by major world events and scientific breakthroughs. Topical antimicrobial burn care has evolved from the use of anecdotal remedies to scientific breakthroughs such as Moyer's successful dilution of silver nitrate solution, Fox's described benefit of silver sulfadiazine use in animal models, and Pruitt's dramatic improvement in post-burn mortality using topical mafenide acetate in burn wounds. The objective of this manuscript is to review the definition of burn wound sepsis and highlight the major developments and breakthroughs in topical burn wound care throughout history. This includes historical events like major wars or domestic fires that have influenced or impacted the understanding and treatment of burn wounds. Newer advances in topical antimicrobial care such as nanosilvers and dressing technologies that improve the morbidity and mortality associated with burn wound sepsis and novel approaches to management will also be discussed. To improve burn care, it is prudent to look to the past and learn from the experiences of those who contributed to the control of burn wound sepsis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: In recent years, it has become apparent that fibrinolytic dysfunction and endotheliopathy develop in up to 40% of patients during the first hours following thermal injury and are associated with poor outcomes and increased resuscitation requirements. Rapidly following burn injury, the fibrinolytic system is activated, with activation generally greater with increased severity of injury. Very high plasma concentrations of plasmin-antiplasmin complex (marker of activation), have been associated with mortality. Patients display hyperfibrinolytic, physiologic/normal or hypofibrinolytic/fibrinolytic shutdown phenotypes, as assessed by viscoelastic assay. Phenotypes change in over 50% of patients during the acute burn resuscitation period, with some patterns (maladaptive) associated with increased mortality risk and others (adaptive, trending toward the physiologic phenotype) associated with survival. Endotheliopathy, as reflected in elevated plasma concentrations of syndecan-1 has also been associated with increased mortality. Here we review the incidence and effects of these responses after burn injury and explore mechanisms and potential interactions with the early inflammatory response. Available data from burn and non-burn trauma suggest that the fibrinolytic, endothelial, and inflammatory systems interact extensively and that dysregulation in one may exacerbate dysregulation in the others. This raises the possibility that successful treatment of one may favorably impact the others., (Copyright © 2024 by the Shock Society.)

Objectives: Fractional ablative CO 2 laser (FLSR) is used to treat hypertrophic scars (HTSs) resulting from burn injuries, which are characterized by factors, such as erythema, contracture, thickness, and symptoms of pain and itch. Traditionally, waiting a year after injury for scar maturation before starting laser treatment has been recommended; however, the potential benefits of earlier intervention have gained popularity. Still, the optimal timing for beginning laser intervention in patients with HTSs remains uncertain. This study aims to evaluate the ideal timing for the initiation of FLSR for HTSs using several qualitative and quantitative assessment measures. It was hypothesized that early intervention would lead to similar improvement trends as later intervention, however, would be more ideal due to the shortened time without symptom relief for patients., Methods: Patients who received three or more laser treatment sessions and completed both pre- and posttreatment evaluations were included in this analysis (n = 69). FLSR treatment was administered at 4-8-week intervals. Patients starting treatment before 6 months after injury were classified as the early-stage intervention group and those beginning treatment at 6-12 months after injury were classified as the late-stage intervention group. Demographic data, including the age of patients at the time of first treatment, age of scars at the time of first treatment, biological sex, ethnicity, Fitzpatrick skin type, and use of laser-assisted drug delivery, were collected by retrospective chart review. Patients were evaluated on six subjective scales and objectively for scar stiffness with durometry. For all scales, higher scores indicate worse scars. A two-way ANOVA, Student's t-test, and Mann-Whitney U-test were used to compare scores from the pre- to posttreatment evaluations., Results: There were no significant differences between the groups for any of the demographic or scar-specific variables; thus, differences in outcome can be attributed to the timing of intervention. Both groups demonstrated an improvement in scars with treatment over time (p < 0.05). Both early- and middle-stage initiation showed scar symptom improvement in five out of six scales. In the late-stage intervention, the Patient and Observer Scar Assessment Scale-Patient average score did not show improvement. In the early-stage intervention, the Vancouver Scar Scale total did not show improvement. Quantitative evaluation of scar stiffness by durometry did not show symptom improvement in either group. The Scar Comparison Scale demonstrated the greatest improvement across groups., Conclusion: Laser treatment led to scar improvement in at least one scale at each stage of initiation. Both intervention timelines resulted in equivalent outcomes, and early intervention should be considered when initiating FLSR treatment in burn scars to alleviate symptoms earlier., (© 2024 The Author(s). Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Objectives: Fractional ablative CO 2 lasers are used clinically to treat cutaneous burn scars with reported varying degrees of effectiveness. It was hypothesized that different laser pulse energy settings may lead to differential gene transcription in a porcine model., Methods: Uninjured skin from red Duroc pigs was treated with a fractional ablative CO 2 laser set to 70, 100, or 120 mJ across the abdomen (n = 4 areas per treatment). Punch biopsies of both treated and untreated sites were taken before treatment (baseline), at 30 min, and at each hour for 6 h and stored in All-Protect tissue reagent. The biopsies were then used to isolate RNA, which was subsequently used in qRT-PCR for eight genes associated with wound healing and the extracellular matrix: CCL2, IL6, FGF2, TIMP1, TIMP3, COL1A2, MMP2, and DCN. RPL13a was used as a housekeeping gene to normalize the eight genes of interest. One-way ANOVA tests were used to assess for differences among laser pulse energies and two-way ANOVA tests were used to assess the differences between treated and untreated areas., Results: While six of the eight genes were upregulated after treatment (p < 0.05), there were no significant differences in gene expression between the different laser pulse energies for any of the eight genes., Conclusion: While laser treatment is correlated with a positive and significant upregulation for six of the eight genes 4 h after intervention, the pulse energy settings of the laser did not lead to a statistically significant difference in gene transcription among the treatment areas. Different laser pulse energies may not be required to induce similar cellular responses in a clinical setting., (© 2024 Wiley Periodicals LLC.)

Background: Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism. Pigs are regarded as the best model with regards to similarity to human skin; however, these studies are expensive, time-consuming, and only small numbers of biologic replicates can be obtained. In addition, local-regional effects of treating wounds that are closely adjacent to one-another with different treatments make assessment of treatment effectiveness difficult in pig models. Therefore, here, a novel nude mouse model of xenografted porcine hypertrophic scar (HTS) cells was developed. This model system was developed to test if supplying hypo-pigmented cells with exogenous alpha melanocyte stimulating hormone (α-MSH) will reverse pigment loss in vivo ., Methods: Dyschromic HTSs were created in red Duroc pigs. Epidermal scar cells (keratinocytes and melanocytes) were derived from regions of hyper-, hypo-, or normally pigmented scar or skin and were cryopreserved. Dermal fibroblasts (DFs) were isolated separately. Excisional wounds were created on nude mice and a grafting dome was placed. DFs were seeded on day 0 and formed a dermis. On day 3, epidermal cells were seeded onto the dermis. The grafting dome was removed on day 7 and hypo-pigmented xenografts were treated with synthetic α-MSH delivered with microneedling. On day 10, the xenografts were excised and saved. Sections were stained using hematoxylin and eosin hematoxylin and eosin (H&E) to assess xenograft structure. RNA was isolated and quantitative real-time polymerase chain reaction (qRT-PCR) was performed for melanogenesis-related genes TYR , TYRP1 , and DCT ., Results: The seeding of HTSDFs formed a dermis that is similar in structure and cellularity to HTS dermis from the porcine model. When hyper-, hypo-, and normally-pigmented epidermal cells were seeded, a fully stratified epithelium was formed by day 14. H&E staining and measurement of the epidermis showed the average thickness to be 0.11 ± 0.07 µm vs. 0.06 ± 0.03 µm in normal pig skin. Hypo-pigmented xenografts that were treated with synthetic α-MSH showed increases in pigmentation and had increased gene expression of TYR , TYRP1 , and DCT compared to untreated controls (TYR: 2.7 ± 1.1 vs. 0.3 ± 1.1; TYRP1: 2.6 ± 0.6 vs. 0.3 ± 0.7; DCT 0.7 ± 0.9 vs. 0.3 ± 1-fold change from control; n = 3)., Conclusions: The developed nude mouse skin xenograft model can be used to study treatments for the skin. The cells that can be xenografted can be derived from patient samples or from pig samples and form a robust dual-skin layer containing epidermis and dermis that is responsive to treatment. Specifically, we found that hypo-pigmented regions of scar can be stimulated to make melanin by synthetic α-MSH in vivo ., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Burn wound healing can be significantly delayed by infection leading to increased morbidity and hypertrophic scarring. An optimal antimicrobial agent would have the ability to kill bacteria without negatively affecting the host skin cells that are required for healing. Currently available products provide antimicrobial coverage, but may also cause reductions in cell proliferation and migration. Cold atmospheric plasma is a partially ionized gas that can be produced under atmospheric pressure at room temperature. In this study a novel handheld Aceso Plasma Generator was used to produce and test Aceso Cold Plasma (ACP) in vitro and in vivo. ACP showed a potent ability to eliminate bacterial load in vitro for a number of different species. Deep partial-thickness and full-thickness wounds that were treated with ACP after burning, after excision, after autografting, and at days 5, 7, and 9 did not show any negative effects on their wound healing trajectories. On par with in vitro analysis, bioburden was decreased in treated wounds vs. control. In addition, metrics of hypertrophic scar such as dyschromia, elasticity, trans-epidermal water loss (TEWL), and epidermal and dermal thickness were the same between the two treatment groups.It is likely that ACP can be used to mitigate the risk of bacterial infection during the phase of acute burn injury while patients await surgery for definitive closure. It may also be useful in treating wounds with delayed re-epithelialization that are at risk for infection and hypertrophic scarring. A handheld cold plasma device will be useful in treating all manner of wounds and surgical sites in order to decrease bacterial burden in an efficient and highly effective manner without compromising wound healing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

The Burn Care Quality Platform (BCQP) consolidates data previously collected from the National Burn Repository and the Burn Quality Improvement Program into a single registry. Its data elements and their associated definitions are tailored to create consistency across other national trauma registries, namely the National Trauma Data Bank implemented by the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP). The BCQP now includes 103 participating burn centers and has captured data from 375,000 total patients as of 2021. With 12,000 patients entered under the current data dictionary, the BCQP represents the largest registry of its kind. On behalf of the American Burn Association Research Committee, the aim of this whitepaper is to provide a succinct overview of the BCQP, showcasing its unique features, strengths, limitations, and relevant statistical considerations. This whitepaper will highlight the resources available to the burn research community and offer insight on proper study design when preparing to conduct a large data set investigation for burn care. All recommendations herein were formulated through the consensus of a multidisciplinary committee and based on the available scientific evidence., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Patients with large burn injuries remain a challenge. The loss of skin barrier integrity and induced immunosuppression after injury increases their vulnerability to infection. Sepsis remains the primary cause of death for burn-injured patients who survive their acute injury and resuscitation. The objective of this work is to describe the current understanding and management of sepsis in the burn-injured patient and newer strategies to approach its management. Current understanding of the systemic inflammatory response to burn injury and sepsis, preventative strategies, and novel research will be discussed. Understanding the origin of burn sepsis from wounds themselves is key to understanding current paradigms. Infection control and management begins from the time of injury and continues throughout the patient's hospital course. The use of personal protective equipment, burn unit design considerations, and optimization of prevention protocols and catheter care all play a role in burn sepsis prevention and management. The emergence of drug-resistant pathogens poses a particular challenge for burn patients due to the chronicity with which their wounds are sometimes open. The difficulty of systemic antibiotics to reach wounds has underscored the need to anticipate resistant organisms moving forward. Antibiotic strategies and newer approaches, such as phage therapy, will be discussed. Multi-omics approaches to understanding burn sepsis have developed in hopes of identifying patients more susceptible or at risk of developing burn sepsis. As with many aspects of burn care, a multidisciplinary, proactive approach to the management of burn sepsis is key to minimizing the morbidity and mortality associated with this complication., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Dyschromia is an understudied aspect of hypertrophic scar (HTS). The use of topical tacrolimus has successfully shown repigmentation in vitiligo patients through promotion of melanogenesis and melanocyte proliferation. It was hypothesized that HTSs treated with topical tacrolimus would have increased repigmentation compared to controls., Methodology: Full-thickness burns in red Duroc pigs were either treated with excision and meshed split-thickness skin grafting or excision and no grafting, and these wounds formed hypopigmented HTSs (n = 8). Half of the scars had 0.1% tacrolimus ointment applied to the scar twice a day for 21 days, while controls had no treatment. Further, each scar was bisected with half incurring fractional ablative CO 2 laser treatment before topical tacrolimus application to induce laser-assisted drug delivery (LADD). Pigmentation was evaluated using a noninvasive probe to measure melanin index (MI) at Days 0 (pretreatment), 7, 14, and 21. At each timepoint, punch biopsies were obtained and fixed in formalin or were incubated in dispase. The formalin-fixed biopsies were used to evaluate melanin levels by H&E staining. The biopsies incubated in dispase were used to obtain epidermal sheets. The ESs were then flash frozen and RNA was isolated from them and used in quantitative reverse transcription polymerase chain reaction for melanogenesis-related genes: Tyrosinase (TYR), TYR-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Analysis of variance test with Šídák's multiple comparisons test was used to compare groups., Results: Over time, within the grafted HTS and the NS group, there were no significant changes in MI, except for Week 3 in the -Tacro group. (+Tacro HTS= pre = 685.1 ± 42.0, w1 = 741.0 ± 54.16, w2 = 750.8 ± 59.0, w3 = 760.9 ± 49.8) (-Tacro HTS= pre = 700.4 ± 54.3, w1 = 722.3 ± 50.7, w2 = 739.6 ± 53.2, w3 = 722.7 ± 50.5). Over time, within the ungrafted HTS and the NS group, there were no significant changes in MI. (+Tacro HTS= pre = 644.9 ± 6.9, w1 = 661.6 ± 3.3, w2 = 650.3 ± 6.2, w3 = 636.3 ± 7.4) (-Tacro HTS= pre = 696.8 ± 8.0, w1 = 695.8 ± 12.3, w2 = 678.9 ± 14.0, w3 = 731.2 ± 50.3). LADD did not lead to any differential change in pigmentation compared to the non-LADD group. There was no evidence of increased melanogenesis within the tissue punch biopsies at any timepoint. There were no changes in TYR, TYRP1, or DCT gene expression after treatment., Conclusion: Hypopigmented HTSs treated with 0.1% tacrolimus ointment with or without LADD did not show significantly increased repigmentation. This study was limited by a shorter treatment interval than what is known to be required in vitiligo patients for repigmentation. The use of noninvasive, topical treatments to promote repigmentation are an appealing strategy to relieve morbidity associated with dyschromic burn scars and requires further investigation., (© 2024 Wiley Periodicals LLC.)

Introduction: Our group previously reported a burn biopsy algorithm (BBA-V1) for categorizing burn wound depth. Here, we sought to promulgate a newer, simpler version of the BBA (BBA-V2)., Methods: Burn wounds undergoing excision underwent 4 mm biopsies procured every 25 cm 2 . Serial still photos were obtained at enrollment and at excision intraoperatively. Burn wounds assessed as likely to heal by 21 days were imaged within 72 h of injury and at 21 days. A sample of 798 burn wound biopsies were classified by both BBAV1 and BBAV2 algorithms. For nonoperative burn wounds, the proportion of healing versus nonhealing pixels at 21 days after injury were compared., Results: The 798 biopsies were classified by BBAV1 as 24% SPT, 47% DPT, 28% FT and by BBAV2 as 3% SPT, 67% DPT, and 30% FT (p < 0.0001). Overall, the proportion of biopsies whose wound reclassification changed from a nonoperative to operative pathway was 21% (95% CI: 18-24%). Nonoperative wounds judged at injury as being SPT contained 12.8 million pixels. Repeat 21-day imaging revealed 11.3 million healed pixels (accuracy = 89.6% (95% CI: 89.59-89.62))., Conclusions: BBA-V2 was associated with a significantly higher concordance with visual assessment for burn wounds clinically judged as deep partial and full thickness., Competing Interests: Declaration of Competing Interest Dr. Phelan serves as a consultant with Avita Medical and SpectralMD. Dr. Holmes has equity positions in Abbott Labs, AbbVie, Change Healthcare Inc, & Imbed Biosciences, and is a consultant for Avita Medical & Stratatech/Mallinckrodt. Dr. Hickerson serves as a consultant for Avita Medical, Vericel, and Stedical. Dr. Cockerell has no disclosures. Dr. Shupp states that he has no competing disclosures relevant to imaging or burn depth determination. Dr. Carter is a stockholder for Permeaderm, Inc. and SpectralMD, and serves as Chief Medical Consultant for SpectralMD. He also serves as a consultant for Avita Medical and Polynovo Ltd. where, in lieu of compensation, all proceeds are donated to a local burn charity to support burn education, survivor programs, outreach, and research., (Copyright © 2023. Published by Elsevier Ltd.)

Dyschromic hypertrophic scar (HTS) is a common sequelae of burn injury, however, its mechanism has not been elucidated. This work is a histological study of these scars with a focus on rete ridges. Rete ridges are important for normal skin physiology, and their absence or presence may hold mechanistic significance in post-burn HTS dyschromia. It was posited that hyper-, and hypo-pigmented areas of scars have different numbers of rete ridges. Subjects with dyschromic burn hypertrophic scar were prospectively enrolled (n = 44). Punch biopsies of hyper-, hypo-, and normally pigmented scar and skin were collected. Biopsies were paraffin embedded, sectioned, stained with H&E, and imaged. The number of rete ridges were investigated. Burn hypertrophic scars that healed without autografts were first investigated. The number of rete ridges was higher in normal skin compared to HTS that was either hypo- (p < 0.01) or hyper-pigmented (p < 0.001). This difference was similar despite scar pigmentation phenotype (p = 0.8687). Autografted hyper-pigmented scars had higher rete ridge ratio compared to non-autografted hyper-pigmented HTS (p < 0.0001). Burn hypertrophihc scars have fewer rete ridges than normal skin. This finding may explain the decreased epidermal adherence to underlying dermis associated with hypertrophic scars. Though, contrary to our hypothesis, no direct link between the extent of dyschromia and rete ridge quantity was observed, the differences in normal skin and hypertrophic scar may lead to further understanding of dyschromic scars., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Although use of thromboelastography (TEG) to diagnose coagulopathy and guide clinical decision-making is increasing, relative performance of different TEG methods has not been well-defined. Rapid-TEG (rTEG), kaolin-TEG (kTEG), and native-TEG (nTEG) were performed on blood samples from burn patients presenting to a regional center from admission to 21 days. Patients were categorized by burn severity, mortality, and fibrinolytic phenotypes (Shutdown [SD], Physiologic [PHYS], and Hyperfibrinolytic [HF]). Manufacturer ranges and published TEG cutoffs were examined. Concordance correlations (Rc) of TEG parameters (R, α-angle, maximum amplitude [MA], LY30) measured agreement and Cohen's Kappa (κ) determined interclass reliability. Patients (n = 121) were mostly male (n = 84; 69.4%), with median age 40 years, median TBSA burn 13%, and mortality 17% (n = 21). Severe burns (≥40% TBSA) were associated with lower admission α-angle for rTEG (P = .03) and lower MA for rTEG (P = .02) and kTEG (P = .01). MA was lower in patients who died (nTEG, P = .04; kTEG, P = .02; rTEG, P = .003). Admission HF was associated with increased mortality (OR, 10.45; 95% CI, 2.54-43.31, P = .001) on rTEG only. Delayed SD was associated with mortality using rTEG and nTEG (OR 9.46; 95% CI, 1.96-45.73; P = .005 and OR, 6.91; 95% CI, 1.35-35.48; P = .02). Admission TEGs showed poor agreement on R-time (Rc, 0.00-0.56) and α-angle (0.40 to 0.55), and moderate agreement on MA (0.67-0.81) and LY30 (0.72-0.93). Interclass reliability was lowest for R-time (κ, -0.07 to 0.01) and α-angle (-0.06 to 0.17) and highest for MA (0.22-0.51) and LY30 (0.29-0.49). Choice of TEG method may impact clinical decision-making. rTEG appeared most sensitive in parameter-specific associations with injury severity, abnormal fibrinolysis, and mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association.)

Background: Neutrophil extracellular trap (NET) formation is a mechanism that neutrophils possess to respond to host infection or inflammation. However, dysregulation of NETosis has been implicated in many disease processes. Although the exact mechanisms of their involvement remain largely unknown, this study aimed to elucidate NET formation over the time course of coronavirus disease 2019 (COVID-19) infection and their possible role in endothelial injury. Patients and Methods: Plasma samples from COVID-19-positive patients were obtained at six timepoints during hospitalization. Neutrophils were extracted from healthy donors and treated with COVID-19-positive patient plasma. Myeloperoxidase (MPO) assay was used to assess for NETosis. Syndecan-1 (SDC-1) enzyme-linked immunosorbent assay (ELISA) was run using the same samples. Immunocytochemistry allowed for further quantification of NETosis byproducts MPO and citrullinated histone 3 (CitH3). The receiver operating characteristic (ROC) curve discriminated between admission levels of SDC-1 and MPO in predicting 30-day mortality and need for ventilator support. Results: Sixty-three patients with COVID-19 were analyzed. Myeloperoxidase was upregulated at day 3, 7, and 14 (p = 0.0087, p = 0.0144, p = 0.0421). Syndecan-1 levels were elevated at day 7 and 14 (p = 0.0188, p = 0.0026). Neutrophils treated with day 3, 7, and 14 plasma expressed increased levels of MPO (p < 0.001). Immunocytochemistry showed neutrophils treated with day 3, 7, and 14 plasma expressed higher levels of MPO (p < 0.001) and higher levels of CitH3 when treated with day 7 and 14 plasma (p < 0.01 and p < 0.05). Admission SDC-1 and MPO levels were found to be independent predictors of 30-day mortality and need for ventilator support. Conclusions: Neutrophil dysregulation can be detrimental to the host. Our study shows that COVID-19 plasma induces substantial amounts of NET formation that persists over the course of the disease. Patients also exhibit increased SDC-1 levels that implicate endothelial injury in the pathogenesis of COVID-19 infection. Furthermore, MPO and SDC-1 plasma levels are predictive of poor outcomes.

Introduction: Literature examining the connection between obesity and burn injuries is limited. This study is a secondary analysis of a multicenter trial data set to investigate the association between burn outcomes and obesity following severe burn injury., Materials and Methods: Body mass index (BMI) was used to stratify patients as normal weight (NW; BMI 18.5-25), all obese (AO; any BMI>30), obese I (OI; BMI 30-34.9), obese II (OII; BMI 35-39.9), or obese III (OIII; BMI>40). The primary outcome examined was mortality. Secondary outcomes included hospital length of stay (LOS), number of transfusions, injury scores, infection occurrences, number of operations, ventilator days, intensive care unit LOS, and days to wound healing., Results: Of 335 patients included for study, 130 were obese. Median total body surface area (TBSA) was 31%, 77 patients (23%) had inhalation injury and 41 patients died. Inhalation injury was higher in OIII than NW (42.1% versus 20%, P = 0.03). Blood stream infections (BSI) were higher in OI versus NW (0.72 versus 0.33, P = 0.03). Total operations, ventilator days, days to wound healing, multiorgan dysfunction score, Acute Physiology and Chronic Health Evaluationscore, hospital LOS, and intensive care unit LOS were not significantly affected by BMI classification. Mortality was not significantly different between obesity groups. Kaplan-Meier survival curves did not significantly differ between the groups (χ 2  = 0.025, P = 0.87). Multiple logistic regression identified age, TBSA, and full thickness burn as significant independent predictors (P < 0.05) of mortality; however, BMI classification itself was not predictive of mortality., Conclusions: No significant association between obesity and mortality was seen after burn injury. Age, TBSA, and percent full- thickness burn were independent predictors of mortality after burn injury, while BMI classification was not., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Following burn injury, alterations in host commensal microbiota across body spaces may leave patients susceptible to opportunistic pathogens and serious sequelae such as sepsis. Generally, studies examining the microbiome postburn have had a limited sample size and lack of longitudinal data, which coupled with experimental and analytic variation, impacts overall interpretation. We performed a meta-analysis of publicly available sequencing data from preclinical and clinical burn studies to determine if there were consistent alterations in the microbiome across various anatomical sites and hosts. Ten human and animal 16S rRNA sequencing studies spanning respiratory, urinary, cutaneous, and gastrointestinal microbiomes were included. Taxonomic classification and alpha and beta diversity metrics were analyzed using QIIME2 v2021.8. Alpha diversity was consistently higher in control samples compared to burn-injured samples which were also different based on host and anatomical location; however, phylogenetic evaluation (ie, Faith PD) elucidated more significant differences compared to taxonomic metrics (ie, Shannon entropy). Beta diversity analysis based on weighted UniFrac showed that rodent specimens clustered less closely to humans than pig samples for both rectal and skin sources. Host species and performing institute were found to have a significant impact on community structure. In rectal samples, bacterial composition in pig and human burn samples included Bacteroidetes, Firmicutes, and Proteobacteria, while rodent samples were dominated by Firmicutes. Proteobacteria and Firmicutes increased on burned skin in each host species. Our results suggest that host species and the performing institute strongly influence microbiome structure. Burn-induced alterations in microbiome diversity and taxa exist across hosts, with phylogenetic metrics more valuable than others. Coordinated, multicenter studies, both clinical and preclinical, within the burn community are needed to more completely realize the diagnostic and therapeutic potential of the microbiome for improving outcomes postburn., (Published by Oxford University Press on behalf of the American Burn Association 2023.)

Mechanisms and timing of hypertrophic scar (HTS) improvement with laser therapy are incompletely understood. Epidermal keratinocytes influence HTS through paracrine signaling, yet they are understudied compared to fibroblasts. It was hypothesized that fractional ablative CO2 laser scar revision (FLSR) would change the fibrotic histoarchitecture of the epidermis in HTS. Duroc pigs (n = 4 FLSR and n = 4 controls) were injured and allowed to form HTS. HTS and normal skin (NS) were assessed weekly by noninvasive skin probes measuring trans-epidermal water loss (TEWL) and biopsy collection. There were 4 weekly FLSR treatments. Immediate laser treatment began on day 49 postinjury (just after re-epithelialization), and early treatment began on day 77 postinjury. Punch biopsies from NS and HTS were processed and stained with H&E. Epidermal thickness and rete ridge ratios (RRR) were measured. Gene and protein expression of involucrin (IVL) and filaggrin (FIL) were examined through qRT-PCR and immunofluorescent (IF) staining. After treatment, peeling sheets of stratum corneum were apparent which were not present in the controls. TEWL was increased in HTS vs NS at day 49, indicating decreased barrier function (P = .05). In the immediate group, TEWL was significantly decreased at week 4 (P < .05). The early group was not significantly different from NS at the prelaser timepoint. After four sessions, the epidermal thickness was significantly increased in treated scars in both FLSR groups (immediate: P < .01 and early: P < .001, n = 8 scars). Early intervention significantly increased RRR (P < .05), and immediate treatment trended toward an increase. There was no increase in either epidermal thickness or RRR in the controls. In the immediate intervention group, there was increased IVL gene expression in HTS vs NS that decreased after FLSR. Eight scars had upregulated gene expression of IVL vs NS levels pretreatment (fold change [FC] > 1.5) compared to four scars at week 4. This was confirmed by IF where IVL staining decreased after FLSR. FIL gene expression trended towards a decrease in both interventions after treatment. Changes in epidermal HTS histoarchitecture and expression levels of epidermal differentiation markers were induced by FLSR. The timing of laser intervention contributed to differences in TEWL, epidermal thickness, and RRR. These data shed light on the putative mechanisms of improvement seen after FLSR treatment. Resolution of timing must be further explored to enhance efficacy. An increased understanding of the difference between the natural history of HTS improvement over time and interventional-induced changes will be critical to justifying the continued approved usage of this treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inhalation injury is a significant cause of morbidity and mortality in the burn patient population. However, the pathogenesis of inhalation injury and its potential involvement in burn shock is not well understood. Preclinical studies have shown endothelial injury, as measured by syndecan-1 (SDC-1) levels, to be involved in the increased vascular permeability seen in shock states. Furthermore, the lung has been identified as a site of significant SDC-1 shedding. Here we aim to characterize the contribution of endotheliopathy caused by inhalation alone in a swine model. When comparing injured animals, the fold change of circulating SDC-1 levels from preinjury was significantly higher at 2, 4, and 6 hours postinjury (P = .0045, P = .0017, and P < .001, respectively). When comparing control animals, the fold change of SDC-1 from preinjury was not significant at any timepoint. When comparing injured animals versus controls, the fold change of SDC-1 injured animals was significantly greater at 2, 4, 6, and 18 hours (P = .004, P = .03, P < .001, and P = .03, respectively). Histological sections showed higher lung injury severity compared to control uninjured lungs (0.56 vs 0.38, P < .001). This novel animal model shows significant increases in SDC-1 levels that provide evidence for the connection between smoke inhalation injury and endothelial injury. Further understanding of the mechanisms underlying inhalation injury and its contribution to shock physiology may aid in development of early, more targeted therapies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: One symptom of hypertrophic scar (HTS) that can develop after burn injury is dyschromia with hyper- and hypopigmentation. There are limited treatments for these conditions. Previously, we showed there is no expression of alpha melanocyte stimulating hormone (α-MSH) in hypopigmented scars, and if these melanocytes are treated with synthetic α-MSH in vitro, they respond by repigmenting. The current study tested the same hypothesis in the in vivo environment using laser-assisted drug delivery (LADD)., Methods: HTSs were created in red Duroc pigs. At Day 77 (pre), they were treated with CO 2 fractional ablative laser (FLSR). Synthetic α-MSH was delivered as a topical solution dissolved in  l-tyrosine (n = 6, treated). Control scars received LADD of  l-tyrosine only (n = 2, control). Scars were treated and examined weekly through Week 4. Digital images and punch biopsies of hyper, hypo-, and normally pigmented scar and skin were collected. Digital pictures were analyzed with ImageJ by tracing the area of hyperpigmentation. Epidermal sheets were obtained from punch biopsies through dispase separation and RNA was isolated. qRT-PCR was run for melanogenesis-related genes: tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Two-way ANOVA with multiple comparisons and Dunnett's correction compared the groups., Results: The areas of hyperpigmentation were variable before treatment. Therefore, data is represented as fold-change where each scar was normalized to its own pre value. Within the LADD of NDP α-MSH + l-tyrosine group, hyperpigmented areas gradually increased each week, reaching 1.3-fold over pre by Week 4. At each timepoint, area of hyperpigmentation was greater in the treated versus the control (1.04 ± 0.05 vs. 0.89 ± 0.08, 1.21 ± 0.07 vs. 0.98 ± 0.24, 1.21 ± 0.08 vs. 1.04 ± 0.11, 1.28 ± 0.11 vs. 0.94 ± 0.25; fold-change from pre-). Within the treatment group, pretreatment, levels of TYR were decreased -17.76 ± 4.52 below the level of normal skin in hypopigmented scars. After 1 treatment, potentially due to laser fractionation, the levels decreased to -43.49 ± 5.52. After 2, 3, and 4 treatments, there was ever increasing levels of TYR to almost the level of normally pigmented skin (-35.74 ± 15.72, -23.25 ± 6.80, -5.52 ± 2.22 [p < 0.01, Week 4]). This pattern was also observed for TYRP1 (pre = -12.94 ± 1.82, Week 1 = -48.85 ± 13.25 [p < 0.01], Weeks 2, 3, and 4 = -34.45 ± 14.64, -28.19 ± 4.98, -6.93 ± 3.05 [p < 0.01, Week 4]) and DCT (pre = -214.95 ± 89.42, Week 1 = -487.93 ± 126.32 [p < 0.05], Weeks 2, 3, and 4 = -219.06 ± 79.33, -72.91 ± 20.45 [p < 0.001], -76.00 ± 24.26 [p < 0.001]). Similar patterns were observed for scars treated with LADD of  l-tyrosine alone without NDP α-MSH. For each gene, in hyperpigmented scar, levels increased at Week 4 of treatment compared to Week 1 (p < 0.01)., Conclusions: A clinically-relevant FLSR treatment method can be combined with topical delivery of synthetic α-MSH and l-tyrosine to increase the area of pigmentation and expression of melanogenesis genes in hypopigmented HTS. LADD of  l-tyrosine alone leads to increased expression of melanogenesis genes. Future studies will aim to optimize drug delivery, timing, and dosing., (© 2023 Wiley Periodicals LLC.)

Resuscitation is required for the management of patients with severe thermal injury. Some of the initial pathophysiologic events following burn injury include an exaggerated inflammatory state, injury to the endothelium, and increased capillary permeability, which all culminate in shock. Understanding these processes is critical to the effective management of patients with burn injuries. Formulas predicting fluid requirements during burn resuscitation have evolved over the past century in response to clinical experience and research efforts. Modern resuscitation features individualized fluid titration and monitoring along with colloid-based adjuncts. Despite these developments, complications from over-resuscitation still occur., (Copyright © 2023 Elsevier Inc. All rights reserved.)

While urinary output (UOP) remains the primary endpoint for titration of intravenous fluid resuscitation, it is an insufficient indicator of fluid responsiveness. Although advanced hemodynamic monitoring (including arterial pulse wave analysis [PWA]) is of recent interest, the validity of PWA-derived indices in burn resuscitation extremes has not been established. The goal of this paper is to test the hypothesis that PWA-derived cardiac output (CO) and stroke volume (SV) indices as well as pulse pressure variation (PPV) and systolic pressure variation (SPV) can play a complementary role to UOP in burn resuscitation. Swine were instrumented with a Swan-Ganz catheter for reference CO and underwent a 40% TBSA burns with varying resuscitation paradigms, and were monitored for 24 hours in an ICU setting under mechanical ventilation. The longitudinal changes in PWA-derived indices were investigated, and resuscitation adequacy was compared as determined by UOP vs PWA indices. The results indicated that PWA-derived indices exhibited trends consistent with reference CO and SV measurements: CO and SV indices were proportional to reference CO and SV, respectively (CO: postcalibration limits of agreement [LoA] = ±24.7 [ml/min/kg], SV: postcalibration LoA = ±0.30 [ml/kg]) while PPV and SPV were inversely proportional to reference SV (PPV: postcalibration LoA = ±0.32 [ml/kg], SPV: postcalibration LoA = ±0.31 [ml/kg]). The results also indicated that PWA-derived indices exhibited notable discrepancies from UOP in determining adequate burn resuscitation. Hence, it was concluded that the PWA-derived indices may have complementary value to UOP in assessing and guiding burn resuscitation., (Published by Oxford University Press on behalf of the American Burn Association 2022.)

The identification of novel treatments for severe burn wounds relies on accurate clinical assessments of the extent of injury. However, evaluation of burn wound depth can be challenging due to the tendency for burn wounds to progress over time in a little-understood process known as 'burn wound conversion'. Local factors affecting the burn wound, such as inflammation, oxidative stress-induced tissue damage, vasostasis and bacterial infections, lead to increased cell death by apoptosis or oncosis, while systemic events may promote burn wound conversion. Acute shock, metabolic derangements, age or immunomodulation can modify cytokine secretion, lower immune responses, decrease blood flow or cause bacterial infection at the burn wound site. Therefore, therapeutic approaches targeting specific mechanisms that reduce cell death, improve wound reperfusion and promote tissue regrowth should favourably enhance burn wound healing, and long-term functional and aesthetic outcomes. Our current understanding of these mechanisms mostly comes from animal studies, underscoring the need for extensive research in humans. A streamlined approach would be to investigate the parallels in other disease states that exhibit ischaemia and potential reperfusion, such as ischaemic stroke and myocardial infarction. Moreover, in view of the limited knowledge available on the subject, the need exists for further clinical research into burn wound conversion and novel target pathways to ameliorate its effects. This review describes events that affect the viability of cells at the burn wound site resulting in burn wound conversion, and identifies potential targets for clinical interventions that may diminish burn wound conversion.

Autologous skin cell suspensions (ASCS) can treat burns of varying depths with the advantage of reduced donor site wound burden. The current standard primary dressing for ASCS is a nonabsorbant, non-adherent, perforated film (control) which has limited conformability over heterogeneous wound beds and allows for run-off of the ASCS. To address these concerns, a novel spray-on polymer formulation was tested as a potential primary dressing in porcine deep partial thickness (DPT) and full thickness (FT) wounds. It was hypothesized that the polymer would perform as well as control dressing when evaluating wound healing and scarring. DPT or FT wounds were treated with either a spray-on poly(lactic-co-glycolic acid) (PLGA) and poly(lactide-co-caprolactone) (PLCL) formulation or control ASCS dressings. Throughout the experimental time course (to day 50), we found no significant differences between polymer and control wounds in % re-epithelialization, graft-loss, epidermal or dermal thickness, or % dermal cellularity in either model. Pigmentation, erythema, elasticity, and trans-epidermal water loss (TEWL), were not significantly altered between the treatment groups, but differences between healing wounds/scars and un-injured skin were observed. No cytotoxic effect was observed in ASCS incubated with the PLGA and PLCL polymers. These data suggest that the novel spray-on polymer is a viable option as a primary dressing, with improved ease of application and conformation to irregular wounds. Polymer formulation and application technique should be a subject of future research., Competing Interests: Conflicts of interest This work was funded by AVITA Medical. M.E. was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R01EB019963. JWS is a consultant for AVITA Medical. The remaining authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Various studies have reported discordant results on the magnitude and direction of burn-induced coagulopathy (BIC), which has recently been associated with multiple organ dysfunction syndrome (MODS) and death. The increased mechanistic understanding of BIC is due, in part, to novel assays that have expanded the armamentarium beyond traditional tests like PT and aPTT. Still, BIC is a dynamic process, and the progression is difficult to define in the thermally-injured. To this end, we aimed to enhance the understanding of burn-induced coagulation abnormalities by employing functional assessments of platelet aggregation, viscoelastic kinetics, and thrombin generation in an extensive burn model in swine. Anesthetized Yorkshire pigs sustained 40% total body surface area (TBSA) full-thickness contact burns and recovered in metabolic cages. Blood was collected at baseline (BL), as well as 6, 24, and 48 h after injury. A significant effect of burn (P < 0.0001) was seen on platelets, with mild thrombocytopenia apparent at 24 h. While slight decreases in aPTT were not significant, rotational thromboelastometry (ROTEM) analysis revealed hypercoagulation 6 and 24 h after burn by a decreased clotting time. Maximum clot firmness increased after burn, but was not statistically significant until 48 h. Hypercoagulation was not supported by platelet aggregation, as the response to ADP was greatly and persistently diminished, and the response to collagen was unchanged. Endogenous thrombin potential was significantly reduced at 6 and 24 h after burn (P < 0.0001), and also correlated with a number of ROTEM parameters and collagen-induced platelet aggregation. In contrast, PT was not correlated with other measured parameters. Taken together, novel coagulation parameters may be more sensitive than PT in characterizing coagulopathy in the setting of burns. The data presented herein makes initial strides to report the natural history of several of these variables over time in a large animal model of extensive burns, indicating early hypercoagulability followed by hypocoagulation. Future work will elucidate the effects of standard of care., Competing Interests: Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army, Uniformed Services University of the Health Sciences, the U.S. Government, the Department of the Army or the Department of Defense., (Published by Elsevier Ltd.)

Introduction: Negative pressure wound therapy (NPWT) is commonly used in open abdomen management, where there may be a simultaneous need for prevention of abdominal hypertension, tamponade of hemorrhage, and continuous fascial tension. The regional pressure dynamics of vacuum dressings are poorly understood., Methods: Three duroc swine underwent mid-line laparotomy and application of vacuum open abdomen dressing, with and without sponge packing. Twenty-five catheters were placed throughout the abdomen to capture and record pressures in each quadrant as the vacuum system was ranged between (-75 mmHg to -200 mmHg pressure). Vital signs and ventilator pressures were measured and recorded concomitantly., Results: No variations in ventilatory pressures or vital signs were observed with any setting. NPWT changed pressure in seven of seventy-five catheters (9%), five of which were related to abdominal packing. When data were grouped into abdominal wall, perihepatic, perisplenic, and deep abdominal regions, there was no significant change in abdominal pressure when packing was absent. With packing, only the abdominal wall region showed a pressure change, reaching a maximum of 20% of the set vacuum pressure., Conclusions: NPWT does only little to change the intraabdominal pressure, except in superficial locations in packed abdomens and does not appear to cause hemodynamic changes in a porcine open abdomen model. While NPWT may play an important role in fluid scavenging and fascial tensioning, there are likely to be few benefits or drawbacks specifically related to negative abdominal pressure in the deep abdomen., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Countermeasures for radiation diagnosis, prognosis, and treatment are trailing behind the proliferation of nuclear energy and weaponry. Radiation injury mechanisms at the systems biology level are not fully understood. Here, mice skin biopsies at h2, d4, d7, d21, and d28 after exposure to 1, 3, 6, or 20 Gy whole-body ionizing radiation were evaluated for the potential application of transcriptional alterations in radiation diagnosis and prognosis. Exposure to 20 Gy was lethal by d7, while mice who received 1, 3, or 6 Gy survived the 28-day time course. A Sammon plot separated samples based on survival and time points (TPs) within lethal (20 Gy) and sublethal doses. The differences in the numbers, regulation mode, and fold change of significantly differentially transcribed genes (SDTGs, p < 0.05 and FC > 2) were identified between lethal and sublethal doses, and down and upregulation dominated transcriptomes during the first post-exposure week, respectively. The numbers of SDTGs and the percentages of upregulated ones revealed stationary downregulation post-lethal dose in contrast to responses to sublethal doses which were dynamic and largely upregulated. Longitudinal up/downregulated SDTGs ratios suggested delayed and extended responses with increasing IR doses in the sublethal range and lethal-like responses in late TPs. This was supported by the distributions of common and unique genes across TPs within each dose. Several genes with potential dosimetric marker applications were identified. Immune, fibrosis, detoxification, hematological, neurological, gastric, cell survival, migration, and proliferation radiation response pathways were identified, with the majority predicted to be activated after sublethal and inactivated after lethal exposures, particularly during the first post-exposure week.

Hypertrophic scar (HTS) formation is a common challenge for patients after burn injury. Dermal microvascular endothelial cells (DMVECs) are an understudied cell type in HTS. An increase in angiogenesis and microvessel density can be observed in HTS. Endothelial dysfunction may play a role in scar development. This study aims to generate a functional and expression profile of HTS DMVECs. We hypothesize that transcript and protein-level responses in HTS DMVECs differ from those in normal skin (NS). HTSs were created in red Duroc pigs. DMVECs were isolated using magnetic-activated cell sorting with ulex europaeus agglutinin 1 (UEA-1) lectin. Separate transwell inserts were used to form monolayers of HTS DMVECs and NS DMVECs. Cell injury was induced and permeability was assessed. Gene expression in HTS DMVECS versus NS DMVECs was measured. Select differentially expressed genes were further investigated. HTS had an increased area density of dermal microvasculature compared to NS. HTS DMVECs were 17.59% less permeable than normal DMVECs (p < 0.05). After injury, NS DMVECs were 28.4% and HTS DMVECs were 18.8% more permeable than uninjured controls (28.4 ± 4.8 vs 18.8 ± 2.8; p = 0.11). PCR array identified 31 differentially expressed genes between HTS and NS DMVECs, of which 10 were upregulated and 21 were downregulated. qRT-PCR and ELISA studies were in accordance with the array. DMVECs expressed a mixed profile of factors that can contribute to and inhibit scar formation. HTS DMVECs have both a discordant response to cellular insults and baseline differences in function, supporting their proposed role in scar pathology. Further investigation of DMVECs is warranted to elucidate their contribution to HTS pathogenesis., (© 2022. The Author(s).)

Staphylococcus aureus , a gram-positive bacterium, causes toxic shock through the production of superantigenic toxins (sAgs) known as Staphylococcal enterotoxins (SE), serotypes A-J (SEA, SEB, etc.), and toxic shock syndrome toxin-1 (TSST-1). The chronology of host transcriptomic events that characterizes the response to the pathogenesis of superantigenic toxicity remains uncertain. The focus of this study was to elucidate time-resolved host responses to three toxins of the superantigenic family, namely SEA, SEB, and TSST-1. Due to the evolving critical role of melanocytes in the host's immune response against environmental harmful elements, we investigated herein the transcriptomic responses of melanocytes after treatment with 200 ng/mL of SEA, SEB, or TSST-1 for 0.5, 2, 6, 12, 24, or 48 h. Functional analysis indicated that each of these three toxins induced a specific transcriptional pattern. In particular, the time-resolved transcriptional modulations due to SEB exposure were very distinct from those induced by SEA and TSST-1. The three superantigens share some similarities in the mechanisms underlying apoptosis, innate immunity, and other biological processes. Superantigen-specific signatures were determined for the functional dynamics related to necrosis, cytokine production, and acute-phase response. These differentially regulated networks can be targeted for therapeutic intervention and marked as the distinguishing factors for the three sAgs.

Introduction: Proposed mechanisms of acute traumatic coagulopathy (ATC) include decreased clotting potential due to factor consumption and proteolytic inactivation of factor V (FV) and activated factor V (FVa) by activated protein C (aPC). The role of FV/FVa depletion or inactivation in burn-induced coagulopathy is not well characterized. This study evaluates FV dynamics following burn and nonburn trauma., Methods: Burn and trauma patients were prospectively enrolled. Western blotting was performed on admission plasma to quantitate levels of FV antigen and to assess for aPC or other proteolytically derived FV/FVa degradation products. Statistical analysis was performed with Spearman's, Chi-square, Mann-Whitney U test, and logistic regression., Results: Burn (n = 60) and trauma (n = 136) cohorts showed similar degrees of FV consumption with median FV levels of 76% versus 73% (P = 0.65) of normal, respectively. Percent total body surface area (TBSA) was not correlated with FV, nor were significant differences in median FV levels observed between low and high TBSA groups. The injury severity score (ISS) in trauma patients was inversely correlated with FV (ρ = -0.26; P = 0.01) and ISS ≥ 25 was associated with a lower FV antigen level (64% versus. 93%; P = 0.009). The proportion of samples showing proteolysis-derived FV was greater in trauma than burn patients (42% versus. 16%; P = 0.0006)., Conclusions: Increasing traumatic injury severity is associated with decreased FV antigen levels, and a greater proportion of trauma patient samples exhibit proteolytically degraded FV fragments. These associations are not present in burns, suggesting that mechanisms underlying FV depletion in burn and nonburn trauma are not identical., (Copyright © 2022. Published by Elsevier Inc.)

Wound infections and sepsis are significant causes of morbidity after burn injury and can be alleviated by early excision and grafting. In situations that preclude early surgery, topical agents allow for a safer delay. Cerium nitrate compounded with silver sulfadiazine (Ce-SSD) is a burn cream that provides broad antibacterial activity, forms a temporary barrier, and promotes re-epithelialization. Methemoglobinemia is a rare, but oft-cited, systemic complication of Ce-SSD. In this retrospective review, 157 patients treated with Ce-SSD between July 2014 and July 2018 were identified, and the monitoring protocol for methemoglobinemia during Ce-SSD treatment was evaluated. The median age was 59 years (interquartile range [IQR], 47-70.5 years), with TBSA of 8.5% (IQR, 3-27), adjusted Baux score of 76 (IQR, 59-94), and inhalation injury present in 9.9% of patients. Primary endpoints included incidence of symptomatic and asymptomatic methemoglobinemia. Of the 9.6% (n = 15) of patients with methemoglobinemia, 73.3% (n = 11) had maximum methemoglobin levels ≥72 hours from the time of the first application. One patient developed clinically significant methemoglobinemia. Patients with TBSA ≥20% were more likely to develop methemoglobinemia (odds ratio 9.318, 95% confidence interval 2.078-65.73, P = .0078); however, neither Ce-SSD doses nor days of exposure were significant predictors. Ce-SSD application to temporize burn wounds until excision and grafting is safe, effective, and, in asymptomatic patients with TBSA <20%, can be used without serial blood gas monitoring. Vigilant monitoring for symptoms should be performed in patients with TBSA ≥20%, but routine blood gases are not necessary., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)