[This corrects the article DOI: 10.1371/journal.pone.0001886.].

Acute coronary thrombosis is a known, but rare, contributor to morbidity and mortality in patients with thermal and electrical injuries. The overall incidence of myocardial infarction among burn patients is 1%, with an in-hospital post-infarction mortality of approximately 67%, whereas the overall mortality rate of the general burn patient population is from 1.4% to 18%. As such, early detection and effective peri-operative management are essential to optimize patient outcomes. Here, we report the details of the management of an adult male patient with a 65% total body surface area severe thermal injury, who developed an ST-elevation myocardial infarction (STEMI) in the resuscitation period. The patient was found to have 100% occlusion of his left anterior descending coronary artery, for which prompt coronary artery stent placement with a drug-eluting stent (DES) was performed. Following stent placement, the patient required dual antiplatelet therapy. The ongoing dual antiplatelet therapy required the development of a detailed peri-operative protocol involving pooled platelets, packed red blood cells, desmopressin (DDAVP™) and intraoperative monitoring of the patient’s coagulation parameters with thromboelastography for three staged operative interventions to achieve complete debridement and skin grafting of his burn wounds.

The treatment of refractory cutaneous wounds remains to be a clinical challenge. There is growing evidence to show that mesenchymal stem cells (MSCs) have great potential in promoting wound healing. However, the therapeutic effects of MSCs are greatly dampened by their poor survival and engraftment in the wounds. To address this limitation, in this study, MSCs were grown into a collagen-glycosaminoglycan (C-GAG) matrix to form a dermis-like tissue sheet, named engineered dermal substitute (EDS). When seeded on C-GAG matrix, MSCs adhered rapidly, migrated into the pores, and proliferated readily. When applied onto excisional wounds in healthy and diabetic mice, the EDS survived well, and accelerated wound closure, compared with C-GAG matrix alone or MSCs in collagen hydrogel. Histological analysis revealed that EDS prolonged the retention of MSCs in the wounds, associated with increased macrophage infiltration and enhanced angiogenesis. RNA-Seq analysis of EDS-treated wounds uncovered the expression of abundant human chemokines and proangiogenic factors and their corresponding murine receptors, suggesting a mechanism of ligand/receptor-mediated signals in wound healing. Thus, our results indicate that EDS prolongs the survival and retention of MSCs in the wounds and enhances wound healing.

The hair follicles (HFs) are barely regenerated after loss in injuries in mammals as well as in human beings. Recent studies have shown that the regenerative ability of HFs is age-related; however, the relationship between this phenomenon and the stem cell niche remains unclear. This study aimed to find a key secretory protein that promotes the HFs regeneration in the regenerative microenvironment. To explore why age affects HFs de novo regeneration, we established an age-dependent HFs regeneration model in leucine-rich repeat G protein-coupled receptor 5 (Lgr5) + /mTmG mice. Proteins in tissue fluids were analyzed by high-throughput sequencing. The role and mechanism of candidate proteins in HFs de novo regeneration and hair follicle stem cells (HFSCs) activation were investigated through in vivo experiments. The effects of candidate proteins on skin cell populations were investigated by cellular experiments. Mice under 3-week-old (3W) could regenerate HFs and Lgr5 HFSCs, which were highly correlated with the immune cells, cytokines, IL-17 signaling pathway, and IL-1α level in the regeneration microenvironment. Additionally, IL-1α injection induced de novo regeneration of HFs and Lgr5 HFSCs in 3W mouse model with a 5 mm wound, as well as promoted activation and proliferation of Lgr5 HFSCs in 7-week-old (7W) mice without wound. Dexamethasone and TEMPOL inhibited the effects of IL-1α. Moreover, IL-1α increased skin thickness and promoted the proliferation of human epidermal keratinocyte line (HaCaT) and skin-derived precursors (SKPs) in vivo and in vitro, respectively. In conclusion, injury-induced IL-1α promotes HFs regeneration by modulating inflammatory cells and oxidative stress-induced Lgr5 HFSCs regeneration as well as promoting skin cell populations proliferation. This study uncovers the underlying molecular mechanisms enabling HFs de novo regeneration in an age-dependent model.

Background: Burn injury is a sudden and traumatic injury that affects a large part of the population worldwide, who are placed at high risk of developing hypertrophic scars (HTS). HTS are a fibrotic scar resulting in painful contracted and raised scarring, affecting mobility in joints and work life, as well as cosmetically. The aim of this research was to enhance our understanding of the systematic response of monocytes and cytokines in wound healing after burn injury, in order to develop novel approaches to prevention and treatment of HTS.Methods: Twenty-seven burn patients and thirteen healthy individuals were recruited in this study. Burn patients were stratified by burn total body surface area (TBSA). Peripheral blood samples were taken post-burn injury. Serum and peripheral blood mononuclear cells (PBMCs) were separated from the blood samples. This research investigated cytokines IL-6, IL-8, IL1RA, IL-10, and chemokine pathways SDF-1/CXCR4, MCP-1/CCR2, RANTES/ CCR5 during the wound healing process in burn patients with varying severity of injuries by using enzyme-linked immunosorbent assays. PBMCs were stained for monocytes and the chemokine receptors by flow cytometry. Statistical analysis was done by one-way ANOVA with a Tukey correction, and regression analysis was performed using Pearson's Correlation analysis.Results: The CD14+ CD16- monocyte subpopulation is larger in patients who developed HTS at 4-7 days. The CD14+ CD16+ monocyte subpopulation is smaller in the first week of injury, where it is similar after 8 days. Burn injury increased CXCR4, CCR2, and CCR5 expressions in CD14+ CD16+ monocytes. Increases in MCP-1 at 0-3 days after burn injury was positively correlated with burn severity. IL-6, IL-8, RANTES, and MCP-1 significantly increased with increasing burn severity.Conclusions: Monocytes and their chemokine receptors, as well as systemic levels of cytokines in wound healing of burn patients and scar development will require ongoing assessment to enhance our understanding of the abnormal wound healing after burn injury.

(1) Background: Exosomes (EXOs) have been considered a new target thought to be involved in and treat wound healing. More research is needed to fully understand EXO characteristics and the mechanisms of EXO-mediated wound healing, especially wound healing after burn injury. (2) Methods: All EXOs were isolated from 85 serum samples of 29 burn patients and 13 healthy individuals. We characterized the EXOs for morphology and density, serum concentration, protein level, marker expression, size distribution, and cytokine content. After a confirmation of EXO uptake by dermal fibroblasts, we also explored the functional regulation of primary human normal skin and hypertrophic scar fibroblast cell lines by the EXOs in vitro, including cell proliferation and apoptosis. (3) Results: EXOs dynamically changed their morphology, density, size, and cytokine level during wound healing in burn patients, which were correlated with burn severity and the stages of wound healing. EXOs both from burn patients and healthy individuals stimulated dermal fibroblast proliferation and apoptosis. (4) Conclusions: EXO features may be important signals that influence wound healing after burn injury; however, to understand the mechanisms by which EXOs regulates the fibroblasts in healing wounds, further studies will be required.

Objective: Patients presenting with total body surface area (TBSA) >40% burns require significant surgical treatment. Two substantial challenges during these surgeries are limiting blood loss and maintaining core temperatures. To overcome these challenges, several techniques have been developed, ranging from the Pitkin syringe method to the pneumatic tourniquet strategy for large-volume hyperthermic insufflation. Here, we compare the pneumatic tourniquet method to a roller pump method for maintenance of intraoperative normothermia and control of bleeding. Methods: We conducted a retrospective chart review of 20 patients presenting with TBSA >40% burns, 10 of whom were treated with the rapid infusion roller pump and 10 of whom were treated with the pneumatic tourniquet technique. Patients from each group were controlled for % TBSA, presence of inhalation injury, age, and date of admission. We reviewed transfusion requirement and the intraoperative temperatures, as well as the average intraoperative drop in temperature. Results: We observed improvement in the infusion volume, operative time, intraoperative temperature drop, minimum intraoperative temperature, estimated blood loss, and amount of required transfusion. Conclusions: Our study suggests that the rapid infusion roller pump technique is capable of achieving superior intraoperative bleeding control and temperature maintenance compared to the pneumatic tourniquet technique, resulting in decreased transfusion requirement.

Background: Recent advances in burn care have significantly improved the survival rate of patients with extensive burn injuries, placing greater emphasis on reconstruction to improve the long-term outcomes of scar deformities. Anterior and lateral neck contractures are common after burn injuries; they limit range of motion, complicate airway management and create significant cosmetic deformities. Traditional methods have been used to release contractures and improve function. However, they are subject to variable results, residual neck tightness, recurrence and suboptimal cosmetic appearance. Microvascular free tissue transfer is a more technically challenging and time-consuming method, but it offers the potential to overcome the long-term limitations of simpler options. In this paper, we present our experience with microvascular free flaps for the release of burn scar contractures of the neck as a potential high-quality permanent solution. Methods: Over a 10-year period, nine free flaps were performed on burn patients with total body surface area (TBSA) burns between 20 and 70%, who developed moderate to severe neck contractures. Four anterolateral thigh (ALT) flaps, four radial forearm free flaps (RFFFs) and one ulnar forearm flap were used to release neck contractures. Results: All nine flaps were completed successfully with significant improvement in the neck's range of motion. Good aesthetic results were achieved with smooth contour and thin coverage. Overall, the patients were satisfied. However, five out of nine cases required at least one secondary procedure for flap defatting to reach optimal results. Conclusion: Post-burn scar contractures of the cervical region compromise the cosmetic appearance and airway security of recovering burn patients, imposing a significant impact on their psychological and functional quality of life. Consequently, cervical contractures can be prioritized when planning reconstruction for burn patients. Free flaps can be considered an important and reliable method of reconstruction for neck contracture deformity following burn injuries.

Guidelines and protocols for orthoses in burn scar contracture rehabilitation are limited. The current study aims to determine the optimal frequency of casting, potentially facilitating the development of a serial casting protocol. Previous literature supporting casting has low generalizability due to methodology limitations. Seven patients with burn scar contracted joints, who did not respond to traditional therapy, were recruited in this study. Patients were serially casted once, three times, or five times a week. Joint range of motion was maximized with stretching and exercise techniques before every new cast application. Across all patients, active range of motion increased from 65.8 ± 27.8° to 108.1 ± 23.3° with casting; or from 57.8 ± 16.2% to 96.7 ± 2.9% of normal. Similarly, scars improved from 9.5 ± 1.5 to 4.9 ± 1.4 on the Modified Vancouver Scar Scale score. This therapeutic effect was achieved within an average of 8.5 ± 3.7 d and 4.0 ± 2.2 new cast applications. Given the study findings, the procedures outlined could be used to develop a standardized serial casting protocol for burn scar contracture rehabilitation.

OBJECTIVES:ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial. SUMMARY BACKGROUND DATA:No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation. METHODS:Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols. RESULTS:Of 379 enrollees, two-thirds (253) were resuscitated with albumin and one-third (126) were resuscitated with crystalloid alone. Albumin patients received more total fluid than Crystalloid patients (5.2 ± 2.3 vs 3.7 ± 1.7 mL/kg/% TBSA burn/24 hours), but patients in the Albumin Group were older, had larger burns, higher admission Sequential Organ Failure Assessment (SOFA) scores, and more inhalation injury. Albumin lowered the in-to-out (I/O) ratio and was started ≤12 hours in patients with the highest initial fluid requirements, given >12 hours with intermediate requirements, and avoided in patients who responded to crystalloid alone. CONCLUSIONS:Albumin use is associated with older age, larger and deeper burns, and more severe organ dysfunction at presentation. Albumin supplementation is started when initial crystalloid rates are above expected targets and improves the I/O ratio. The fluid received in the first 24 hours was at or above the Parkland Formula estimate.

Significance: Hypertrophic scars (HTS) are a fibroproliferative disorder that occur following deep dermal injury and affect up to 72% of burn patients. These scars result in discomfort, impaired mobility, disruption of normal function and cosmesis, and significant psychological distress. Currently, there are no satisfactory methods to treat or prevent HTS, as the cellular and molecular mechanisms are complex and incompletely understood. This review summarizes the biology of proteins in the dermal extracellular matrix (ECM), which are involved in wound healing and hypertrophic scarring. Recent Advances: New basic research continues toward understanding the diversity of cellular and molecular mechanisms of normal wound healing and hypertrophic scarring. Broadening the understanding of these mechanisms creates insight into novel methods for preventing and treating HTS. Critical Issues: Although there is an abundance of research conducted on collagen in the ECM and its relationship to HTS, there is a significant gap in understanding the role of proteoglycans and their specific isoforms in dermal fibrosis. Future Directions: Exploring the biological roles of ECM proteins and their unique isoforms in HTS, mature scars, and normal skin will further the understanding of abnormal wound healing and create a more robust understanding of what constitutes dermal fibrosis. Research into the biological roles of ECM protein isoforms and their regulation during wound healing warrants a more extensive investigation to identify their distinct biological functions in cellular processes and outcomes.

Insufflation of epinephrine-containing solutions (clysis) has shown to decrease blood loss in burn surgery. Current delivery methods are associated with significant cost and may predispose burn patients to hypothermia. This was a proof-of-concept study to evaluate a novel surgeon-operated clysis delivery system. Our initial experience with a novel fluid management system is presented. Temperature, pressure, and volume of clysis was recorded. Patient and burn factors were evaluated and complications collected. Finally, a cost-effectiveness analysis was conducted. Thirty-seven consecutive cases comprising 22 adult patients (15/22, 68% male), with a mean age of 49 years (+/−19) were reviewed. The mean % total body surface area of all patients was 39 (+/−21.7). The mean temperature, pressure, and volume of administered clysis was 32.2 degrees Celsius (+/−4.4), 265.04 mmHg (+/−56.17), and 5805.8 mL (+/−4844.4), respectively. The mean dose of epinephrine administered was 14.5 mg (+/−12.1). The mean temperature variability was 1.1 °C (+/−1.2). The total mean of packed red blood cells (PRBC) transfused was 507.6 mL (+/−624.4). There were no recorded complications. We identified a cost savings of CAD 20,766 over the cases examined, compared to our conventional clysis delivery technique. This novel technique provides rapid and safe infiltration of warmed clysis in burn surgery. We were able to maintain intra-operative euthermia. In addition, this technique may be transfusion-sparing. The introduction of this method of clysis administration was associated with significant cost-savings. Future randomized study is necessary.

Significance: Hypertrophic scars (HTS) and keloids are common after thermal injuries and other trauma to deep regions of dermis of the skin. These abnormal scars can cause contractures and the thick masses of scar tissue that result in functional and cosmetic impairment. Management of these dermal fibrotic conditions includes a wide range of medical and surgical treatments, which can be time consuming, only partially effective, and often uncomfortable for patients.Recent Advances: The molecular pathophysiology of HTS has become more understood over the past two decades, where thermal injury to the reticular dermis results in an inflammatory response, fibrogenic growth factor release, and the formation of a dermal scar with increased collagen and proteoglycan composition in an abnormal morphology. Lasers are becoming a widely used form of treatment for these types of scars; however, the evidence for the beneficial effects of laser treatments and the understanding of their mechanism of action are still evolving.Critical Issues: Paradoxically, laser delivery of thermal energy to the skin is suggested to improve scar remodeling and wound healing, yet HTS is a well-recognized complication of excessive thermal energy delivered by laser treatments. This review aims to examine the current evidence for the use of lasers for HTS, and to investigate the molecular mechanisms where re-injury of a burn scar from laser treatment could result in overall improvements in scar quality.Future Directions: Improved design of clinical trials for the treatment of scarring in the future will evolve from new methodology and models of HTS in animals and humans.

Multiple animal species and approaches have been used for modeling different aspects of burn care, with some strategies considered more appropriate or translatable than others. On April 15, 2021, the Research Special Interest Group of the American Burn Association held a virtual session as part of the agenda for the annual meeting. The session was set up as a pro/con debate on the use of small versus large animals for application to four important aspects of burn pathophysiology: burn healing/conversion, scarring, inhalation injury, and sepsis. For each of these topics, two experienced investigators (one each for small and large animal models) described the advantages and disadvantages of using these preclinical models. The use of swine as a large animal model was a common theme due to anatomic similarities with human skin. The exception to this was a well-defined ovine model of inhalation injury; both of these species have larger airways which allow for incorporation of clinical tools such as bronchoscopes. However, these models are expensive and demanding from labor and resource standpoints. Various strategies have been implemented to make the more inexpensive rodent models appropriate for answering specific questions of interest in burns. Moreover, modeling burn-sepsis in large animals has proven difficult. It was agreed that the use of both small and large animal models has merit for answering basic questions about the responses to burn injury. Expert opinion and the ensuing lively conversations are summarized herein, which we hope will help inform experimental design of future research.

Introduction: Brachial plexus blockade (BPB) is a procedure of growing popularity amongst surgeons and anaesthesiologists involved with upper limb surgery. The safety and benefit in hand surgery is unclear. Methods: A retrospective chart review was performed examining all operative hand cases over a 2-year period. All cases of metacarpal open reduction internal fixation (ORIF) were included. Cases were excluded if paediatric patient, additional procedures performed, and/or a decreased LOC. Parametric statistical tests were performed. Results: In total, 54 cases with general anaesthesia (GA) and 48 cases with BPB were identified for the study (n = 102). The average total time from operating theatre to discharge was 245 ± 72 minutes in GA group and 195 ± 54 minutes in BPB ( P < .001). Of those who had a GA, 47/54 patients required analgesia post-operatively versus 12/48 in the BPB ( P < .001). Of all, 25/52 and 5/48 patients required anti-emetics post-operatively in the GA and BPB groups, respectively ( P < .001). Need for any parenteral medication post-operatively was also significantly different ( P < .001). Conclusion: This is the first study to specifically examine anaesthetic techniques for ORIF of hand fractures; adding to the body of literature establishing BPB as a safe and efficient method of anaesthesia.

Skin grafting is often the only treatment for skin trauma when large areas of tissue are affected. This surgical intervention damages the deeper dermal layers of the skin with implications for wound healing and a risk of scar development. Photobiomodulation (PBM) therapy modulates biological processes in different tissues, with a positive effect on many cell types and pathways essential for wound healing. This study investigated the effect of fluorescent light energy (FLE) therapy, a novel type of PBM, on healing after skin grafting in a dermal fibrotic mouse model. Split-thickness human skin grafts were transplanted onto full-thickness excisional wounds on nude mice. Treated wounds were monitored, and excised xenografts were examined to assess healing and pathophysiological processes essential for developing chronic wounds or scarring. Results demonstrated that FLE treatment initially accelerated re-epithelialization and rete ridge formation, while later reduced neovascularization, collagen deposition, myofibroblast and mast cell accumulation, and connective tissue growth factor expression. While there was no visible difference in gross morphology, we found that FLE treatment promoted a balanced collagen remodeling. Collectively, these findings suggest that FLE has a conceivable effect at balancing healing after skin grafting, which reduces the risk of infections, chronic wound development, and fibrotic scarring.

Currently, engineered skin substitutes (ESS) are unable to regenerate cutaneous appendages. Recent studies have shown that skin-derived precursors (SKPs), which are extensively available, have the potential to induce hair follicle neogenesis. Here, we demonstrate that ESS consisting of culture-expanded SKPs and epidermal stem cells (Epi-SCs) reconstitute the skin with hair follicle regeneration after grafting into nude mice. SKPs seeded in a C-GAG matrix proliferated and expressed higher levels of hair induction signature genes—such as Akp2, Sox2, CD133 and Bmp6—compared to dermal fibroblasts. Moreover, when ESS prepared by seeding a mixture of culture-expanded murine SKPs and human adult Epi-SCs into a C-GAG matrix was grafted into full-thickness skin wounds in nude mice, black hairs were generated within 3 weeks. Immunofluorescence analysis showed that the SKPs were localized to the dermal papillae of the newly-formed hair follicle. Our results indicate that SKPs can serve as the hair-inductive cells in ESS to furnish it with hair genesis potential

Survival from burn injury has improved considerably over the past two decades such that the quality of life of the victim of thermal injuries has become a major concern. Severe proliferative scarring or hypertrophic scarring (HTS) is an all too frequent complication of burn wound healing that severely compromises quality of life for surviving burn victims. Prevention of such scarring in burn patients involves better understanding of the pathophysiology of scar formation, development of newer methods for determining depth of burn injury and earlier and advanced surgical interventions. Many established and evolving novel treatments for HTS in patients after thermal injury exist and include antifibrotic pharmaceuticals and cellular-based therapies as reviewed herein.

Hypertrophic scars are a dermal form of fibroproliferative diseases that develop after skin trauma to the deep dermis.Dysfunction of the chemokine network can result in prolonged inflammation, abnormal blood vessel development, and a fibrotic wound-healing environment.To understand the role of the chemokine signaling in pathological scar formation, the inhibitory effects of scar formation by chemokine inhibitors of AMD3100, Maraviroc, and CAS445479-97-0 were investigated using a mouse model of dermal fibrosis, in which human split-thickness skin grafts were transplanted into full-thickness excision wounds in the dorsal of athymic nude mice, and the human skin grafts developed scars morphologically and histologically similar to human hypertrophic scars.The mice were treated with one of chemokine inhibitors from 5 days after grafting daily for 1 week and thereafter once a week.Mouse wounds were monitored, and scar tissues were collected at 2, 6, and 12 weeks after grafting for further histological and biochemical analysis.AMD3100 and Maraviroc reduced wound contraction.AMD3100 improved collagen orientation and up-regulated mRNA level of decorin in the early phase of wound healing.AMD3100, CAS445479-97-0 and Maraviroc reduced scar thickness, macrophage recruitment and myofibroblast formation, and down-regulated gene expressions of type I collagen in the early phase, heat shock protein 47 in the late phase, alpha-smooth muscle actin, and connective tissue growth factor throughout the whole phase of wound healing.Blocking chemokine pathways significantly improved scars in this dermal fibrotic model, which can be potential therapeutic targets for hypertrophic scars.

Hypertrophic scars (HTS) are a common complication following burn injuries with prolonged inflammation. They do not respond well to current treatment options including mechanical, biomolecular and surgical therapies. Toll-like receptor (TLR) 2 and 4 respond to microbes and damaged endogenous ligands to trigger pro-inflammatory pathways, and they are expressed more in HTS fibroblasts compared to normal skin fibroblasts. TLR2 responds to microbial lipoteichoic acid (LTA) while TLR4 responds to microbial lipopolysaccharide (LPS) and endogenous ligands. We investigated the role of burn tissue and small leucine-rich proteoglycans (decorin and biglycan) in the stimulation of TLR2 and TLR4 pathways using cells stably transfected with TLR2 or TLR4 linked to a reporter system. Normal skin (n = 5) was collected post-abdominoplasty, and burn eschar samples (n = 18) were collected from 18 patients between 0 and 14 days post-burn. We found that burn tissue stimulates TLR2 activity significantly more than normal tissue and contains significantly higher levels of LTA. Burn tissue was a stronger stimulator of TLR4 than was normal skin. Burn tissue samples' stimulation of TLR4 and TLR2 correlated. The time post-burn (0-14 days) of wound tissue sampling correlated positively but moderately with TLR2 and TLR4 simulation. In comparison to the dose-dependent effects of natural decorin or biglycan on TLR4 activation, their denatured forms exhibited stronger or weaker stimulation, respectively. They were not potent stimulators of TLR2. TLR2 and TLR4 stimulation is not limited to bacteria in wounds and likely involves multiple endogenous damage-associated molecular patterns. Insight into mechanisms of HTS will facilitate the development of future targeted therapies to modify wound progression and provide benefits to patients suffering with HTS and other fibroproliferative disorders.