Search

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 degrees to 108.1 ± 23.3 degrees 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 days 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.

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.

Objectives ABRUPT was a prospective, non-interventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, in order 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 versus 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. Conclusion 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.

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.

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.

Significance: Hypertrophic scars (HTS) and keloids are common after thermal injuries and other trauma to the deep regions of the dermis of the skin. These abnormal scars can cause contractures and ...

Transplantation of human xenografts onto immunocompromised mice is a powerful research tool for studying wound healing. However, differences in healing between humans and mice and their small size limit this model. We determined whether human cadaver skin xenografts transplanted onto pigs with severe combined immune deficiency (SCID) would survive and not be rejected. Meshed (1:1.5), cryopreserved human cadaver skin was transplanted onto 10 partial thickness dermatome wounds in each of two normal domestic pigs and two SCID pigs. Autografts (n = 2/animal) from the four animals were used as controls. In normal pigs, all autografts were engrafted and healed with a minimal, if any, inflammation and scarring. All human xenografts were rejected by the normal pigs within 5-11 days and associated with an intense T-cell inflammatory response. In contrast, both autografts and xenografts were engrafted and survived the 28-day study in the SCID pigs with a minimal inflammation and no gross scarring.

Objectives Studies suggest that a restrictive transfusion strategy is safe in burns, yet the efficacy of a restrictive transfusion policy in massive burn injury is uncertain. Our objective: compare outcomes between massive burn (≥60% total body surface area (TBSA) burn) and major (20–59% TBSA) burn using a restrictive or a liberal blood transfusion strategy. Methods Patients with burns ≥20% were block randomized by age and TBSA to a restrictive (transfuse hemoglobin Results Three hundred and forty-five patients received 7,054 units blood, 2,886 in massive and 4,168 in restrictive. Patients were similar in age, TBSA, and inhalation injury. The restrictive group received less blood (45.57 ± 47.63 vs. 77.16 ± 55.0, p < 0.03 massive; 11.0 ± 16.70 vs. 16.78 ± 17.39, p < 0.001) major). In massive burn, the restrictive group had fewer ventilator days (p < 0.05). Median ICU days and LOS were lower in the restrictive group; wound healing, mortality, and infection did not differ. No significant outcome differences occurred in the major (20–59%) group (p > 0.05). Conclusions: A restrictive transfusion strategy may be beneficial in massive burns in reducing ventilator days, ICU days and blood utilization, but does not decrease infection, mortality, hospital LOS or wound healing.

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.

Orbital compartment syndrome (OCS) is a rare but devastating complication of over-resuscitation in burn patients that may lead to permanent visual loss. The purpose of this study was to 1) present a series of burn patients with OCS and 2) survey practice patterns of monitoring intra-ocular pressure (IOP) during burn resuscitation. Cases of OCS at two American Burn Association (ABA)–verified burn centers were retrospectively reviewed. Patients were included if they 1) required lateral canthotomy/cantholysis for elevated IOPs or 2) developed blindness on admission unrelated to any other ocular pathology. Data were collected on demographics, burn characteristics, fluid administration, ophthalmologic findings, and complications. An eight-item electronic survey was distributed by email through the ABA to all physician members. Twelve patients with OCS were identified, with a mean age of 47.8 ± 12.4 years and TBSA of 63.7 ± 18.6%. Mean fluid resuscitation at 24 hours was 4.9 ± 1.6 ml/kg/%TBSA or 0.29 ± 0.06 liter/kg. Eight patients underwent canthotomy/cantholysis for OCS, whereas four were later found to have visual loss. A total of 83 (14%) ABA physicians responded to the survey. IOP was routinely measured by 23% of respondents during acute burn resuscitation. OCS appears to have developed despite a relatively low 24-hour ml/kg/% burn resuscitation volume, but with a relatively higher cumulative (liter/kg) fluid volume. Their survey found that monitoring of IOP during burn resuscitation is not routinely performed by the majority of providers. Taken together, the present study suggests clinical guidelines to recognize this complication of over-resuscitation.

Supplemental Digital Content is available in the text., Summary: Objective evidence for the role of inhibition of collagen cross-linking in human scar using a nontoxic topical inhibitor, 1,4-diaminobutane (1,4 DAB), in patients with scars at risk for hypertrophic scar formation is presented. The authors used a concentration of 1,4 DAB of 0.8% (weight/volume) in a cream base similar to Glaxal Base. Application was once per day at night. The control was treated with cream base alone. In treatment phase studies at 2 months, tissue biopsies were performed and used to determine a therapeutic effect biochemically in paired scars harvested chosen with typical hypertrophic scars at two major treatment centers. Tissue transglutaminase activity revealed a significant reduction of the ε-(γ-glutamyl)lysine cross-links in the treated scars: 7.96 ± 1.51 pmol/µmol amino acid versus 14.78 ± 3.52 pmol/µmol amino acid. A subset of paired scars (n = 15) was also analyzed for soluble procollagen type III amino propeptide. The effect was a significant increase in procollagen type III amino propeptide in the scars treated with 1,4 DAB compared with sham-treated scars: 47.75 ± 4.6 µg/mg wet weight versus 39.08 ± 6.02 µg/mg wet weight, respectively. Levels of tissue 1,4 DAB was found to be twice as high in the presence of the active cream versus in the tissue of the control group. In subsequent prophylaxis studies, the authors treated 44 breast reduction patients prospectively with active cream to one or the other side in a double-blind randomized fashion. Hardness (in grams) measured using a Rex Durometer at 6 and 12 weeks postoperatively along with photographs were analyzed. The mean value ± SD of 24.98 ± 1.2 g on the active side versus 31.76 ± 1.1 g on the sham side was significantly different (p < 0.05). The patient scale scores of the Patient and Observer Scar Assessment Scale were also requested by survey in a responding 27-patient subgroup at a minimum 1 year postoperatively, and the differences between the two sides were found to be statistically significant, where the mean on the active side was 14.07 ± 1.34 and the mean on the sham side was 21.41 ± 1 (p < 0.05). The results are evidence to support the use of this agent in prevention of hypertrophic scars. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Macrophages play a key role in the wound healing process and can be divided into classically activated macrophages (M1) and alternatively activated macrophages (M2). Fibroblasts maintain the physical integrity of connective tissue, participate in wound closure as well as produce and remodel extracellular matrix. Macrophages have a close relationship with fibroblasts by increasing the production of matrix metalloproteinase-1 (MMP-1) for faster wound closure and remodeling and myofibroblast differentiation from fibroblasts. In this study, resting state (M0), M1 and M2 macrophages differentiated from the human monocytic THP-1 cell line were used to co-culture with human dermal fibroblasts (HDF) for 48, 96 and 144 hours to investigate the effect of macrophages subsets on the fibrogenic activity of fibroblasts. The differentiation and polarization from THP-1 cells to M0, M1 and M2 macrophages were characterized by flow cytometry and cell cycle analysis. Cell sorting was performed to purify M0 and M2 macrophages. Cell proliferation, collagen synthesis, myofibroblast formation, gene expression of anti-fibrotic and pro-fibrotic factors, MMP-1 activity, and cytokine concentration were investigated. Results showed differentiation of M0 and polarization of M1 and M2 macrophages. M2 macrophages promoted the fibrogenic activities of co-cultured HDF by facilitating cell proliferation, increasing the collagen content, alpha-smooth muscle actin expressed cells, expression of the pro-fibrotic genes and concentration of M2 macrophage related factors, as well as decreasing the expression of the anti-fibrotic genes and MMP-1 activity. These findings reinforce the pro-fibrotic role of M2 macrophages, suggesting therapeutic strategies in fibrotic diseases should target M2 macrophages in the future.

Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen–anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro. TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5+ HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5+ HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding.

After studying this article, the participant should be able to: 1. Explain the epidemiology of severe burn injury in the context of socioeconomic status, gender, age, and burn cause. 2. Describe challenges with burn depth evaluation and novel methods of adjunctive assessment. 3. Summarize the survival and functional outcomes of severe burn injury. 4. State strategies of fluid resuscitation, endpoints to guide fluid titration, and sequelae of overresuscitation. 5. Recognize preventative measures of sepsis. 6. Explain intraoperative strategies to improve patient outcomes, including hemostasis, restrictive transfusion, temperature regulation, skin substitutes, and Meek skin grafting. 7. Translate updates in the pathophysiology of hypertrophic scarring into novel methods of clinical management. 8. Discuss the potential role of free tissue transfer in primary and secondary burn reconstruction.Management of burn-injured patients is a challenging and unique field for plastic surgeons. Significant advances over the past decade have occurred in resuscitation, burn wound management, sepsis, and reconstruction that have improved outcomes and quality of life after thermal injury. However, as patients with larger burns are resuscitated, an increased risk of nosocomial infections, sepsis, compartment syndromes, and venous thromboembolic phenomena have required adjustments in care to maintain quality of life after injury. This article outlines a number of recent developments in burn care that illustrate the evolution of the field to assist plastic surgeons involved in burn care.

Scarring is a natural response following wound healing and includes mature and pathological scars. Pathological scars such as hypertrophic scars (HTS) and keloids are commonly seen in burns and other traumatic injuries to the deep dermis of the skin. HTS are hypervascular, red, raised, and pruritic scars, which are normally confined to the boundary of the original injury, and can remodel into mature scars but often over prolonged periods of time. The development of HTS can lead to physical disfigurement, contractures, and loss of function. Despite many treatment options, there are no modalities available for the prevention or complete reversal of scar formation. Therefore, an updated cellular and molecular understanding of the pathophysiology of HTS is important in order to develop promising novel therapies that can benefit the patients and their care-providers.

In order to increase one's competitiveness in the current job market, Canadian plastic surgery graduates may complete additional degrees and multiple fellowships. The authors sought to determine the impact of this additional training on the practice profile of recent graduates and determine the current state of job satisfaction among this group.An anonymous cross-sectional online survey was created and sent to all 250 graduates of Canadian plastic surgery residencies from 2005 to 2015. Demographics were collected and questions grouped into clinical, teaching, research, and administrative components. Questions pertaining to job satisfaction were also included.The response rate to the survey was 39%. Sixty-nine (71%) respondents had permanent attending positions at the time of survey completion, while the remaining 28 respondents did not. Among those with permanent positions, 59 (86%) completed at least one fellowship and 30 (43%) have an advanced degree. Of those who did fellowship training, 76% practice primarily in their area of subspecialty. Having an advanced degree showed a trend to a higher percentage of practice dedicated to research (5.6% vs 1.9%;The majority of recent Canadian plastic surgery graduates are undergoing fellowship training and are practicing primarily in their fields of subspecialty training. Having a postgraduate degree was associated with a higher number of publications per year as an attending surgeon. Job satisfaction is high among recent graduates.Afin d’accroître leur compétitivité sur le marché du travail, les diplômés canadiens en chirurgie plastique peuvent obtenir d’autres diplômes et de multiples postdoctorats. Les auteurs ont cherché à établir les retombées de cette formation supplémentaire sur le profil de pratique des récents diplômés ainsi que la satisfaction au travail des membres de ce groupe.Les 250 diplômés d’une résidence en chirurgie plastique au Canada entre 2005 et 2015 ont reçu un sondage transversal anonyme en ligne. Les chercheurs ont recueilli les données démographiques et ont regroupé les questions dans les volets de la clinique, de l’enseignement, de la recherche et de l’administration. Il y avait également des questions sur la satisfaction au travail.Le taux de réponse au sondage s’élevait à 39 %. Soixante-neuf répondants (71 %) occupaient un poste permanent au moment du sondage, contrairement aux 28 autres. Chez ceux qui occupaient un poste permanent, 59 (86 %) avaient effectué au moins un postdoctorat et 30 (43 %) possédaient un diplôme avancé. Parmi ceux qui avaient fait un postdoctorat, 76 % exerçaient surtout dans leur domaine de surspécialité. Un diplôme avancé s’associait à une tendance vers un pourcentage plus élevé de pratiques vouées à la recherche (5.6 % par rapport à 1.9 %;La majorité des récents diplômés en chirurgie plastique au Canada étudient au postdoctorat et exercent surtout dans leur domaine de surspécialité. Le postdoctorat s’associait à un plus grand nombre de publications par année de la part des chirurgiens. La satisfaction au travail était élevée chez les récents diplômés.

Patients with major burn injuries typically require numerous blood transfusions. It is not known if an inhalation injury (INHI) directly influences the need for blood transfusion. The purpose of this study was to determine whether INHI increases the amount of blood transfused to major burn patients. A secondary analysis from the Transfusion Requirement in Burn Care Evaluation (TRIBE) study was conducted. Patients with INHI were compared with patients without INHI. The number of red blood cell (RBC) transfusions per day (RBC per day) between INHI and No INHI was analyzed with a multivariable regression. Patients with INHI (n = 78) had significantly larger burns (P = .0004), larger full-thickness burns (P = .0007), greater admission APACHE score (P < .0001), higher admission multiple organ dysfunction scores (P < .0001), and were transfused more RBC per day (P = .009) than No INHI patients (n = 267). In the multivariable regression analysis, RBC per day was significantly associated with the %TBSA burn (P < .0001), age of the patient (P = .004), the need for more than 1 day of mechanical ventilation (P < .0001), the occurrence of at least one blood stream infection (BSI; P = .044), and being assigned to the liberal transfusion arm of TRIBE (P < .001) but not the presence of INHI (P = .056). The null hypothesis that INHI exerts no influence on the amount of blood transfused could not be rejected. Larger burn size, advanced patient age, mechanical ventilation, and BSIs are important determinants of the blood transfusion rate in major burn patients.

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

Recent studies show that designer peptide nanofibers can mimic properties of extracellular matrix molecules, promising great potential as scaffold materials for tissue engineering. However, their ability in supporting organogenesis has not been studied. Here we examined the effect of self-assembling peptide hydrogels in supporting skin derived precursors (SKPs) in hair follicle neogenesis. We found that hydrogels formed by RADA16, PRG which contains RGD, and particularly the combination of RADA16 and PRG (RADA-PRG) enhanced SKP proliferation. Notably, the RADA-PRG hydrogel, which exhibited advantages of RADA16 in adequate nanofiber formation and PRG in providing the integrin binding sequence, exhibited superior effects in enhancing SKP survival, expression of hair induction signature genes such as Akp2 and Bmp6, and more importantly de novo hair genesis in mice. Thus our results suggest that RADA-PRG may serve as a novel scaffold material for stem cell transplantation and tissue engineering.

Hypertrophic scars are caused by trauma or burn injuries to the deep dermis and can cause cosmetic disfigurement and psychological issues. Studies suggest that M2-like macrophages are pro-fibrotic and contribute to hypertrophic scar formation. A previous study from our lab showed that M2 macrophages were present in developing hypertrophic scar tissues in vivo at 3-4 weeks after wounding. In this study, the effect of systemic macrophage depletion on scar formation was explored at subacute phase of wound healing. Thirty-six athymic nude mice that received human skin transplants were randomly divided into macrophage depletion group and control group. The former received intraperitoneal injections of clodronate liposomes while the controls received sterile saline injections on day 7, 10, and 13 postgrafting. Wound area, scar thickness, collagen abundance and collagen bundle structure, mast cell infiltration, myofibroblast formation, M1, and M2 macrophages together with gene expression of M1 and M2 related factors in the grafted skin were investigated at 2, 4, and 8 weeks postgrafting. The transplanted human skin from the control group developed contracted, elevated, and thickened scars while the grafted skin from the depletion group healed with significant less contraction and elevation. Significant reductions in myofibroblast number, collagen synthesis, and hypertrophic fiber morphology as well as mast cell infiltration were observed in the depletion group compared to the control group. Macrophage depletion significantly reduced M1 and M2 macrophage number in the depletion group 2 weeks postgrafting as compared to the control group. These findings suggest that systemic macrophage depletion in subacute phase of wound healing reduces scar formation, which provides evidence for the pro-fibrotic role of macrophages in fibrosis of human skin as well as insight into the potential benefits of specifically depleting M2 macrophages in vivo.

The modified Meek micrografting technique constitutes a rapid and efficient surgical approach for the skin coverage of extensive full-thickness burn injuries. A total of 10 burn patients (mean 68 ± 9.2% TBSA) admitted to our burn unit required one or more Meek micrografting procedures (mean 2.2 ± 0.5) to cover in average 43.4 ± 11.6% TBSA (range between 10 and 75% TBSA). This goal was achieved using a donor site area ranging between 2.5 and 18% TBSA. All patients developed local infection to Pseudomona aeruginosa (75%), Stenotrophomona maltophilia (25%), methicillin-resistant Staphylococcus aureus (12.5%), and Acinetobacter baumannii (12.5%). Thus, the average of Meek regrafting after graft-take failure was 13.1 ± 6.4% TBSA (median: 9%; range from 0 to 36%). The period to obtain stable definitive wound closure was in average of 67.2 ± 21 days post injury. The modified Meek micrografting provides a reliable and versatile method for the coverage of large burn wounds with limited autograft donor sites and is now routinely used in our institution. Its systematic use improves operating times and overall outcomes reducing the number of surgeries, increasing the percentage of graft take, and decreasing the length of stay.

Background Proliferative scars in nude mice have demonstrated morphologic and histologic similarities to human hypertrophic scar. Gene knockout technology provides the opportunity to study the effect of deleting immune cells in various disease processes. The authors' objective was to test whether grafting human skin onto T-cell receptor (TCR) αβ-/-γδ-/-, recombination activating gene (RAG)-1-/-, and RAG-2γ-/-c-/- mice results in proliferative scars consistent with human hypertrophic scar and to characterize the morphologic, histologic, and cellular changes that occur after removing immune cells. Methods Nude TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice (n = 20 per strain) were grafted with human skin and euthanized at 30, 60, 120, and 180 days. Controls (n = 5 per strain) were autografted with mouse skin. Scars and normal skin were harvested at each time point. Sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry for anti-human leukocyte antigen-ABC, α-smooth muscle actin, decorin, and biglycan. Results TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice grafted with human skin developed firm, elevated scars with histologic and immunohistochemical similarities to human hypertrophic scar. Autografted controls showed no evidence of pathologic scarring. Knockout animals demonstrated a capacity for scar remodeling not observed in nude mice where reductions in α-smooth muscle actin staining pattern and scar thickness occurred over time. Conclusions Human skin transplanted onto TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice results in proliferative scars with morphologic and histologic features of human hypertrophic scar. Remodeling of proliferative scars generated in knockout animals is analogous to changes in human hypertrophic scar. These animal models may better represent the natural history of human hypertrophic scar.

Introduction Recovery from burn scar contracture demands significant time and resources from patients and healthcare providers. Few studies have explored how serial casting improves recovery. The aim is to present preliminary data illustrating the benefits of serial casting in burn scar contracture rehabilitation. Methods Six burn patients (8 joints) that did not respond to traditional conservative therapy were included. Joints were x-rayed to rule out heterotopic ossification/joint abnormality before casting. Patients were casted 5x, 3x or 1x/week. Initial session consisted of measuring baseline range of motion (ROM) prior to physiotherapy intervention (PTI) (heat, active ROM with end range overpressure, joint glides, and progressive resistive exercises) and plaster cast application by Occupational Therapy. Following sessions involved measuring ROM post cast removal, and before PTI and new cast application. Scar contractures were photographed weekly and assessed using the Modified Vancouver Scar Scale (MVSS). Results On average, casting started 93.67±20.31 days post burn injury and lasted 8.90±1.23 days. Mean time between cast changes was 2.30±0.25 days; on average, each joint was casted 4.30±0.65 times. MVSS score (pre/post serial casting:9.70±0.47 / 4.70±0.42, p< 0.0001) and ROM as a percentage of total (pre/post serial casting:56.30±5.12% / 96.40±0.90%, p< 0.0001) showed improvements from pre to post casting. Post casting, average ROM gained was 43.70±6.60 degrees and average percentage of ROM regained was 96.38±0.87%. Each joint consumed a mean of 6.56±1.22 therapy hours and $45.13±12.15 in materials. Conclusions Serial casting produced rapid gains in ROM to near full ROM in burn scar contracted joints. Correspondingly scar pliability, height, and pigmentation improved. Serial casting can be effective and initiated early in scar maturation. Applicability of Research to Practice Serial casting can be a standard technique in rehabilitation of burn scar contracture. It is easy to adopt due to low material cost, easy therapist training, and low time demands from patients and therapists. It can delay or prevent the need for contracture release surgery (in the case of 3 patients). Based on therapist observations, it can lead to increased treatment compliance due to rapid effectiveness.

Objectives Major trials examining storage age of blood transfused to critically ill patients administered relatively few blood transfusions. We sought to determine if the storage age of blood affects outcomes when very large amounts of blood are transfused. Design A secondary analysis of the multicenter randomized Transfusion Requirement in Burn Care Evaluation study which compared restrictive and liberal transfusion strategies. Setting Eighteen tertiary-care burn centers. Patients Transfusion Requirement in Burn Care Evaluation evaluated 345 adults with burns greater than or equal to 20% of the body surface area. We included only the 303 patients that received blood transfusions. Interventions The storage ages of all transfused red cell units were collected during Transfusion Requirement in Burn Care Evaluation. A priori measures of storage age were the the mean storage age of all transfused blood and the proportion of all transfused blood considered very old (stored ≥ 35 d). Measurements and main results The primary outcome was the severity of multiple organ dysfunction. Secondary outcomes included time to wound healing, the duration of mechanical ventilation, and in-hospital mortality. There were 6,786 red cell transfusions with a mean (± SD) storage age of 25.6 ± 10.2 days. Participants received a mean of 23.4 ± 31.2 blood transfusions (range, 1-219) and a mean of 5.3 ± 10.7 units of very old blood. Neither mean storage age nor proportion of very old blood had any influence on multiple organ dysfunction severity, time to wound healing, or mortality. Duration of ventilation was significantly predicted by both mean blood storage age and the proportion of very old blood, but this was of questionable clinical relevance given extreme variability in duration of ventilation (adjusted r ≤ 0.01). Conclusions Despite massive blood transfusion, including very old blood, the duration of red cell storage did not influence outcome in burn patients. Provision of the oldest blood first by Blood Banks is rational, even for massive transfusion.

Hypertrophic scars (HTS) are caused by trauma or burn injuries to the deep dermis and are considered fibrosis in the skin. Monocytes, M1 and M2 macrophages are mononuclear phagocytes. Studies suggest that M2 macrophages are profibrotic and might contribute to HTS formation. Our lab has established a human HTS-like nude mouse model, in which the grafted human skin develops red, raised, and firm scarring, resembling HTS seen in humans. In this study, we observed the natural behavior of mononuclear phagocyte system in this nude mouse model of dermal fibrosis at multiple time points. Thirty athymic nude mice received human skin grafts and an equal number of mice received mouse skin grafts as controls. The grafted skin and blood were harvested at 1, 2, 3, 4, and 8 weeks. Wound area, thickness, collagen morphology and level, the cell number of myofibroblasts, M1- and M2-like macrophages in the grafted skin, as well as monocyte fraction in the blood were investigated at each time points. Xenografted mice developed contracted and thickened scars grossly. The xenografted skin resembled human HTS tissue based on enhanced thickness, fibrotic orientation of collagen bundles, increased collagen level, and infiltration of myofibroblasts. In the blood, monocytes dramatically decreased at 1 week postgrafting and gradually returned to normal in the following 8 weeks. In the xenografted skin, M1-like macrophages were found predominantly at 1-2 weeks postgrafting; whereas, M2-like macrophages were abundant at later time points, 3-4 weeks postgrafting coincident with the development of fibrosis in the human skin tissues. This understanding of the natural behavior of mononuclear phagocytes in vivo in our mouse model provides evidence for the role of M2-like macrophages in fibrosis of human skin and suggests that macrophage depletion in the subacute phases of wound healing might reduce or prevent HTS formation.

Summary Background Post-surgical pyoderma gangrenosum (PSPG) presents as a rapidly expanding cutaneous ulcer at a site of surgery with potentially devastating consequences. We systematically reviewed the English and foreign language literature to identify risk factors for PSPG and propose a management strategy. Methods A systematic review was completed in PubMed, Medline, Embase, and Cochrane Database for all published reports of PSPG from January 1946 to June 2013. We manually examined bibliographies for relevant references and used Google Translate for articles in foreign languages, including Italian, Japanese, German, Dutch, Turkish, Spanish, Chinese, Dutch, Russian, Portuguese, and Czech. Results We identified 220 cases of PSPG (mean age 52.8 years, range 5–85 years). Thirty-seven patients (16.8%) had a history of pyoderma gangrenosum, nineteen (8.6%) had a hematologic disorder such as leukemia or lymphoma, thirteen (5.9%) had inflammatory bowel disease, and eight (3.6%) had rheumatoid arthritis. PSPG occurred most commonly after breast (25%), cardiothoracic (14%), abdominal (14%), and obstetric (13%) surgeries. The most common breast procedures were bilateral reduction mammoplasty (45%), breast reconstruction (25%), and lumpectomy or mastectomy (11%). Signs of wound complication occurred on average 7.0 days after surgery. Nineteen patients (8.6%) at risk for PSPG received perioperative corticosteroids during skin grafting or later surgeries with a favorable outcome. Conclusions Patients with a history of pyoderma gangrenosum, rheumatoid arthritis, inflammatory bowel disease, or hematologic malignancy who are undergoing breast, cardiothoracic, or abdominal surgeries should be carefully observed for post-operative ulceration at incision sites. Debridement should not be performed before dermatologic consultation to assess for PSPG. Patients at risk of PSPG undergoing breast surgery may benefit from perioperative prednisone to prevent PSPG which can lead to destructive wound enlargement and significant scarring.

Heterotopic ossification (HO) is a complication of musculoskeletal injury characterized by the formation of mature bone in soft tissues. The etiology of HO is unknown. We investigated the role of bone marrow derived progenitor cells in HO pathophysiology. We isolated the cells from HO specimens by cell explantation. Using flow cytometry and immunofluorescence microscopy, we found that 35 to 65% of the HO cells exhibit a bone marrow derived fibrocyte profile consisting in spindle-shaped morphology associated with type 1 pro-collagen and LSP1 expression. When cultured in osteogenic differentiation medium, active machinery for bone mineralization (high gene expression of Anx2, TNAP, and Pit-1), and calcium/phosphate deposits were found. Interestingly, interferon-alpha 2b significantly reduced the proliferation rate and COL1 gene expression in HO cells. We have characterized a novel subset of bone marrow derived progenitor cells in the HO specimens. The findings from this research study will provide new insights into the development of HO in burn patients.

Fibrosis affects most organs, it results in replacement of normal parenchymal tissue with collagen-rich extracellular matrix, which compromises tissue architecture and ultimately causes loss of function of the affected organ. Biochemical pathways that contribute to fibrosis have been extensively studied, but the role of biomechanical signaling in fibrosis is not clearly understood. In this study, we assessed the effect keratinocytes have on the biomechanical characteristics and pore microstructure of tissue engineered skin made with superficial or deep dermal fibroblasts in order to determine any biomaterial-mediated anti-fibrotic influences on tissue engineered skin. Tissue engineered skin with deep dermal fibroblasts and keratinocytes were found to be less stiff and contracted and had reduced number of myofibroblasts and lower expression of matrix crosslinking factors compared to matrices with deep fibroblasts alone. However, there were no such differences between tissue engineered skin with superficial fibroblasts and keratinocytes and matrices with superficial fibroblasts alone. Also, tissue engineered skin with deep fibroblasts and keratinocytes had smaller pores compared to those with superficial fibroblasts and keratinocytes; pore size of tissue engineered skin with deep fibroblasts and keratinocytes were not different from those matrices with deep fibroblasts alone. A better understanding of biomechanical characteristics and pore microstructure of tissue engineered skin may prove beneficial in promoting normal wound healing over pathologic healing.

The stabilization of endotracheal tubes in the burn population presents many problems. Access to the face for dressings, debridements, and the use of topical antimicrobials prevent adequate stabilization of the endotracheal tube with commonly used methods. Conventional methods have an increased risk of shifting, which can lead to injury to the friable burned tissue or unplanned extubation. To prevent these complications, alternative methods using the dentition to stabilize the endotracheal tube have been described. Here, we present our technique of using Ivy loops to secure the endotracheal tube. It is a simple method with low complications that provides a strong stabilization of the tube while giving access to the face.La stabilisation de la sonde trachéale au sein de la population des grands brûlés s’associe à de nombreux problèmes. Il est impossible d’utiliser les méthodes habituelles pour la stabiliser, afin de conserver l’accès au visage pour les pansements, les débridements et l’application d’antimicrobiens topiques. La méthode classique accroît le risque de délogement, qui peut susciter des blessures aux tissus brûlés friables et une extubation non planifiée. Afin de prévenir ces complications, il existe une autre méthode de stabilisation de la sonde trachéale, qui fait appel à la dentition. Dans la présente étude, les chercheurs exposent leur technique d’utilisation des ligatures d’Ivy pour sécuriser la sonde trachéale. C’est une méthode simple, au faible taux de complications, qui assure une stabilisation élevée de la sonde tout en maintenant l’accès au visage.

ObjectiveOur objective was to compare outcomes of a restrictive to a liberal red cell transfusion strategy in 20% or more total body surface area (TBSA) burn patients. We hypothesized that the restrictive group would have less blood stream infection (BSI), organ dysfunction, and mortality.BackgroundPatients with major burns have major (>1 blood volume) transfusion requirements. Studies suggest that a restrictive blood transfusion strategy is equivalent to a liberal strategy. However, major burn injury is precluded from these studies. The optimal transfusion strategy in major burn injury is thus needed but remains unknown.MethodsThis prospective randomized multicenter trial block randomized patients to a restrictive (hemoglobin 7-8 g/dL) or liberal (hemoglobin 10-11 g/dL) transfusion strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes.ResultsEighteen burn centers enrolled 345 patients with 20% or more TBSA burn similar in age, TBSA burn, and inhalation injury. A total of 7054 units blood were transfused. The restrictive group received fewer blood transfusions: mean 20.3 ± 32.7 units, median = 8 (interquartile range: 3, 24) versus mean 31.8 ± 44.3 units, median = 16 (interquartile range: 7, 40) in the liberal group (P < 0.0001, Wilcoxon rank sum). BSI incidence, organ dysfunction, ventilator days, and time to wound healing (P > 0.05) were similar. In addition, there was no 30-day mortality difference: 9.5% restrictive versus 8.5% liberal (P = 0.892, χ test).ConclusionsA restrictive transfusion strategy halved blood product utilization. Although the restrictive strategy did not decrease BSI, mortality, or organ dysfunction in major burn injury, these outcomes were no worse than the liberal strategy (Clinicaltrials.gov identifier NCT01079247).

Inflammatory cells exert crucial influence on wound healing, while exploration is still desired to get further insight into the key factors that promote the process. In the present study, we performed comparative microarray data analysis of the three types of inflammatory cells isolated from skin wounds and focused on differentially expressed secreted factors. Gene Ontology enrichment and receptor analysis indicated that 11 genes of secreted factors in Ly6C+ inflammatory macrophages and 27 genes of secreted factors in neutrophils exhibited higher (≥ 5-fold) expression, and all these factors were considered as candidates with potentially important role in keratinocyte activation. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that TNF and IL17 signaling pathways were activated by Ly6C+ inflammatory macrophages secreted cytokines, while TGF-beta, HIF-1, NF-κB, and Rap 1 signaling pathways and pathways regulating pluripotency of stem cells were highly involved with neutrophils secreted cytokines. Taking TNF as an example, the source of the cytokine and its impact on keratinocytes were verified by immunofluorescence, gene knockout mice, and quantitative phosphoproteomics. Collectively, this study has indicated distinctively expressed cytokines in three inflammatory cells, which is helpful in identifying key factors in inducing keratinocyte signaling and in wound healing.

Hypertrophic scar (HTS) is a common outcome of deep dermal wound healing mainly followed mechanical, chemical, and thermal injuries in the skin. Because of the lack of the most effective prevention and treatment, it is particularly important to establish an ideal dermal animal model for improving the understanding of the pathogenesis and exploring therapeutic approaches of HTS. Compared to other dermal fibrotic animal models in rabbits, red Duroc pigs, guinea pigs, rats, and mice, the approach that uses normal human split-thickness skin grafted onto nude or other immunodeficient mice which develop scars that resemble human HTS offers the advantages of lower cost, easier manipulation, and shorter research period. In this chapter, we will introduce the detailed procedures to create the ideal dermal fibrotic mouse model.

Hypertrophic scar and contracture in burn patients is a complex process. Contributing factors include critical injury depth and activation of key cell subpopulations, including deep dermal fibroblasts, myofibroblasts, fibrocytes, and T-helper cells, which cause scarring rather than regeneration. These cells influence each other via cellular profibrotic and antifibrotic signals, which help to determine the outcome. These cells also both modify and interact with extracellular matrix of the wound, ultimately forming hypertrophic scar. Current treatments reduce hypertrophic scar formation or improve remodeling by targeting these pathways and signals.

Hypertrophic scar (HTS) is a common outcome of deep dermal wound healing mainly followed mechanical, chemical, and thermal injuries in the skin. Because of the lack of the most effective prevention and treatment, it is particularly important to establish an ideal dermal animal model for improving the understanding of the pathogenesis and exploring therapeutic approaches of HTS. Compared to other dermal fibrotic animal models in rabbits, red Duroc pigs, guinea pigs, rats, and mice, the approach that uses normal human split-thickness skin grafted onto nude or other immunodeficient mice which develop scars that resemble human HTS offers the advantages of lower cost, easier manipulation, and shorter research period. In this chapter, we will introduce the detailed procedures to create the ideal dermal fibrotic mouse model.

Effective prevention and treatment of hypertrophic scars (HTSs), a dermal form of fibrosis that frequently occurs following thermal injury to deep dermis, are unsolved significant clinical problems. Previously, we have found that stromal cell-derived factor 1/CXCR4 signaling is up-regulated during wound healing in burn patients and HTS tissue after thermal injury. We hypothesize that blood-borne mononuclear cells are recruited into wound sites after burn injury through the chemokine pathway of stromal cell-derived factor 1 and its receptor CXCR4. Deep dermal injuries to the skin are often accompanied by prolonged inflammation, which leads to chemotaxis of mononuclear cells into the wounds by chemokine signaling where fibroblast activation occurs and ultimately HTS are formed. Blocking mononuclear cell recruitment and fibroblast activation, CXCR4 antagonism is expected to reduce or minimize scar formation. In this study, the inhibitory effect of CXCR4 antagonist CTCE-9908 on dermal fibrosis was determined in vivo using a human HTS-like nude mouse model, in which split-thickness human skin is transplanted into full-thickness dorsal excisional wounds in athymic mice, where these wounds subsequently develop fibrotic scars that resemble human HTS as previously described. CTCE-9908 significantly attenuated scar formation and contraction, reduced the accumulation of macrophages and myofibroblasts, enhanced the remodeling of collagen fibers, and down-regulated the gene and protein expression of fibrotic growth factors in the human skin tissues. These findings support the potential therapeutic value of CXCR4 antagonist in dermal fibrosis and possibly other fibroproliferative disorders.

Hypertrophic scarring is extremely common and is the source of most morbidity related to burns. The biology of hypertrophic healing is complex and poorly understood. Multiple host and injury factors contribute, but protracted healing of partial thickness injury is a common theme. Hypertrophic scarring and heterotopic ossification may share some basic causes involving marrow-derived cells. Several traditional clinical interventions exist to modify hypertrophic scar. All have limited efficacy. Laser interventions for scar modification show promise, but as yet do not provide a definitive solution. Their efficacy is only seen when used as part of a multimodality scar management program.

Heterotopic ossification (HO) is a clinical condition of ectopic bone formation in soft tissue. This clinical entity has been associated with genetic disorders, traumatic injuries, and musculoskeletal surgeries. In this regard, functional impairments secondary to scar contractures seen in burn injuries may be exacerbated with underlying HO. The appropriate prevention or management of this complication is crucial to optimize outcome in burn patients. This clinical study reviews the incidence of HO in our burned patients, diagnostic methods, therapeutic approaches including surgical timing and techniques.