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Keloid tissues contain inflammatory cells and upregulated pro-inflammatory cytokines. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediate cellular responses to these cytokines. We performed a systematic review on the role of the JAK–STAT pathway in keloid pathogenesis and the evidence for JAK–STAT inhibitors in keloid treatment. The search combined the terms (1) keloid and (2) JAK or TYK or STAT and included MeSH terms and synonyms. Two reviewers screened the articles and assessed the full texts on eligibility. Data were collected on the tested drugs and molecules, the type of cells and tissues used in the experiments, and study findings on the association between the JAK–STAT pathway and keloid cells and tissues. A total of twenty preclinical studies were included. Eleven preclinical studies proved that STAT3 expression and phosphorylation are enhanced in keloid tissue and keloid fibroblasts. Thirteen different JAK and/or STAT inhibitors were investigated. Tested drugs inhibited keloid progression as demonstrated by different processes, including reduced collagen production, cell proliferation and migration, increased cell cycle arrest and apoptosis, enhanced antioxidant responses, decreased (paracrine) signalling, and decreased profibrotic gene expression. No clinical studies have been published to date. Preclinical studies indicate a role for the JAK–STAT pathway in keloid pathogenesis and a potential role for JAK–STAT inhibitors in keloid treatment. The effect of these drugs should be further investigated on relevant biomarkers in a human keloid skin model, preferably including immune cells besides keloid fibroblasts and keratinocytes and in clinical studies.

Patients with extensive and complex wounds due to Necrotizing Soft-Tissue Infections (NSTI) may be referred to hospitals with a burn centre. This study describes the characteristics, outcomes, as well as diagnostic challenges of these patients. Patients admitted to three burn centres for the treatment of NSTI in a 5-year period were included. Eighty patients (median age 54 years, 60% male) were identified, of whom 30 (38%) were referred by other centres, usually after survival of the initial septic phase. Those referred from other centres, compared to those primarily admitted to the study hospital, were more likely to have group A streptococcal involvement (62% versus 35%, p=0.02), larger wounds (median 7% versus 2% total body surface area, p

Background Necrotizing soft tissue infections (NSTI) affect long-term quality of life in survivors. Different approaches to debridement may influence quality of life. The aim of this study was to assess the current practice of the debridement of NSTI in the Netherlands. Methods An animated, interactive online survey was distributed among general surgeons and plastic surgeons in the Netherlands. Two NSTI-cases were presented, followed by questions regarding the preferred surgical approach. Case one described a woman with a swollen, red leg, with signs of sepsis and without visible necrosis. Case two described an immunocompromised man with septic shock syndrome and extensive necrosis. Results In total 232 responses were included (143 general surgeons, 89 plastic surgeons). In case one, 32% chose to preserve all skin, while 17% chose to resect all skin above the affected fascia, including normal-looking skin. In case two, all participants resected necrotic skin, and most (88%) also blue discolored skin. While 32% did not resect more than blue discolored and necrotic skin, 35% also resected red-colored skin, and 21% all skin overlying the affected fascia, including normal colored skin. Respondents working in a hospital with a burn center tended to preserve more skin, whereas plastic surgeons chose more often for skin resection compared to general surgeons. Conclusions By using a novel approach to a survey, the authors demonstrate the existence of extensive practice variety regarding the approach to debridement of NSTI among Dutch general and plastic surgeons. Consensus is needed, followed by targeted education of surgeons.

This study evaluates the short- and long-term effect of burns on children’s height and weight, by comparing their pre and postburn growth trajectory. We invited children (≤17 years old), who sustained a burn requiring surgical treatment or admission at one of the Dutch burn centers in 2013 (n = 175). As well as children who sustained a severe burn, covering >10% of the total body surface area (TBSA), throughout 2009–2018 (n = 228). Data was collected from a survey on health-related topics, Youth Health Care records, and the Dutch Burn Repository R3. For all participants, height and weight were converted to Z-scores using Dutch reference values. Linear mixed modeling, nested on the individual level, was used to examine the associations between burns and children’s height and weight Z-scores. Children’s height and weight Z-scores remained within the normal range throughout the study period. During the first-year postburn, children’s height and weight Z-scores decreased by −0.21 (95% CI −0.41, −0.01) and −0.23 (95% CI −0.46, −0.04), respectively. Beyond the first-year postburn, estimates were consistent with a positive linear association between burn size and the overall effect of burns on participants’ height and weight Z-scores. This included a modest, but statistically significant, effect among participants with a burn covering ≤4.5% and >14.0% of the TBSA. Sensitivity analyses did not alter our findings. In conclusion, children were on track or even surpassed their growth potential. Our findings could therefore be considered reassuring to patients, parents, and clinicians.

Long-term scar formation is an important adverse consequence in children with burns, however, information regarding scar quality in the long-term is lacking. Therefore, we evaluated scar quality and its predictors in children with burns 5–7 years after injury. Parents of children with mild/intermediate burns (≤10% total body surface area burned), and of children with severe burns (>10% burned) completed the patient scale of the Patient and Observer Scar Assessment Scale (POSAS 2.0) for their children's—in their opinion—worst scar 5–7 years post-burn. Outcomes and predictive factors of scar quality were studied, and, for children with severe burns, POSAS parent scores were compared with observer scores. We included 103 children with mild/intermediate burns and 28 with severe burns (response rate: 51%). Most children (87%) had scars that differed from normal skin, with most differences reported for colour, and least for pain. Except for colour, children with severe burns had significantly higher scores (difference 0–2 points) on all scar characteristics (representing poorer scar quality) compared with children with mild/intermediate burns. Parent POSAS scores were on average 2.0–2.6 points higher compared to observer scores. Number of surgeries predicted both the mean POSAS and the mean overall opinion of a scar. In conclusion, 5–7 years post-burn, the scar of the majority of children differed from normal skin, especially on the characteristic colour. The uncovered insights are useful in counselling of children and their parents on expectations of the final outcome of their (children's) scar(s), and help in further targeting scar prevention strategies for the individual child.

The relationship between infrastructure, technology, model of care, and human resources influences patient outcomes and safety, staff productivity and satisfaction, retention of personnel, and treatment and social costs. This concept underpins the need for evidence-based design and has been widely adopted to inform hospital infrastructure planning. The aim of this review is to establish evidence-based, universally applicable key features of a burn unit that support function in a comprehensive patient-centered model of care. A literature search in medical, architectural, and engineering databases was conducted. Burn associations’ guidelines and relevant articles published in English, between 1990 and 2020, were included, and the available evidence is summarized in the review. Few studies have been published on burn unit design in the past 30 years. Most of them focus on the role of design in infection control and prevention and consist primarily of descriptive or observational reports, opportunistic historical cohort studies, and reviews. The evidence available in the literature is not sufficient to create a definitive infrastructure guideline to inform burn unit design, and there are considerable difficulties in creating evidence that will be widely applicable. In the absence of a strong evidence base, consensus guidelines on burn unit infrastructure should be developed, to help healthcare providers, architects, and engineers make informed decisions, when designing new or renovated facilities.

The mechanical behavior of dermal tissues is unarguably recognized for its diagnostic ability and in the last decades received a steadily increasing interest in dermatology practices. Among the various methods to investigate the mechanics of skin in clinical environments, suction-based ones are especially noteworthy, thanks to their qualities of minimal invasiveness and relative simplicity of setups and data analysis. In such experiments, structural visualization of the sample is highly desirable, both in its own right and because it enables elastography. The latter is a technique that combines the knowledge of an applied mechanical stimulus and the visualization of the induced deformation to result in a spatially resolved map of the mechanical properties, which is particularly important for an inhomogeneous and layered material such as skin. We present a device, designed for clinical trials in dermatology practices, that uses a handheld probe to (1) deliver a suction-based, controlled mechanical stimulus and (2) visualize the subsurface structure via optical coherence tomography. We also present a device-agnostic data-analysis framework, consisting of a Python library, released in the public domain. We show the working principle of the setup on a polymeric model and on a volunteer's skin.

This study investigates patients’ access to surgical care for burns in a low- and middle-income setting by studying timeliness, surgical capacity, and affordability. A survey was conducted in a regional referral hospital in Manyara, Tanzania. In total, 67 patients were included. To obtain information on burn victims in need of surgical care, irrespective of time lapsed from the burn injury, both patients with burn wounds and patients with contractures were included. Information provided by patients and/or caregivers was supplemented with data from patient files and interviews with hospital administration and physicians. In the burn wound group, 50% reached a facility within 24 hours after the injury. Referrals from other health facilities to the regional referral hospital were made within 3 weeks for 74% in this group. Of contracture patients, 74% had sought healthcare after the acute burn injury. Of the same group, only 4% had been treated with skin grafts beforehand, and 70% never received surgical care or a referral. Together, both groups indicated that lack of trust, surgical capacity, and referral timeliness were important factors negatively affecting patient access to surgical care. Accounting for hospital fees indicated patients routinely exceeded the catastrophic expenditure threshold. It was determined that healthcare for burn victims is without financial risk protection. We recommend strengthening burn care and reconstructive surgical programs in similar settings, using a more comprehensive health systems approach to identify and address both medical and socioeconomic factors that determine patient mortality and disability.

Background Tangential excision of burned tissue followed by skin grafting is the cornerstone of burn surgery. Hydrosurgery has become popular for tangential excision, with the hypothesis that enhanced preservation of vital dermal tissue reduces scarring. The aim of this trial was to compare scar quality after hydrosurgical versus conventional debridement before split-skin grafting. Methods A double-blind randomized within-patient multicentre controlled trial was conducted in patients with burns that required split-skin grafting. One wound area was randomized to hydrosurgical debridement and the other to Weck knife debridement. The primary outcome was scar quality at 12 months, assessed with the observer part of the Patient and Observer Scar Assessment Scale (POSAS). Secondary outcomes included complications, scar quality, colour, pliability, and histological dermal preservation. Results Some 137 patients were randomized. At 12 months, scars of the hydrosurgical debrided wounds had a lower POSAS observer total item score (mean 2.42 (95 per cent c.i. 2.26 to 2.59) versus 2.54 (95 per cent c.i. 2.36 to 2.72; P = 0.023)) and overall opinion score (mean 3.08 (95 per cent c.i. 2.88 to 3.28) versus 3.30 (95 per cent c.i. 3.09–3.51); P = 0.006). Patient-reported scar quality and pliability measurements were significantly better for the hydrosurgically debrided wounds. Complication rates did not differ between both treatments. Histologically, significantly more dermis was preserved with hydrosurgery (P Conclusion One year after surgery scar quality and pliability was better for hydrosurgically debrided burns, probably owing to enhanced histological preservation of dermis. Registration number Trial NL6085 (NTR6232 (http://www.trialregister.nl)).

Healthcare is undergoing a profound technological and digital transformation and has become increasingly complex. It is important for burns professionals and researchers to adapt to these developments which may require new ways of thinking and subsequent new strategies. As Einstein has put it: 'We must learn to see the world anew'. The relatively new scientific discipline "Complexity science" can give more direction to this and is the metaphorical open door that should not go unnoticed in view of the burn care of the future. Complexity sciences studies 'why the whole is more than the sum of the parts'. It studies how multiple separate components interact with each other and their environment and how these interactions lead to 'behavior of the system'. Biological systems are always part of smaller and larger systems and exhibit the behavior of adaptivity, hence the name complex adaptive systems. From the perspective of complexity science, a severe burn injury is an extreme disruption of the 'human body system'. But this disruption also applies to the systems at the organ and cellular level. All these systems follow principles of complex systems. Awareness of the scaling process at multilevel helps to understand and manage the complex situation when dealing with severe burn cases. The aim of this paper is to create awareness of the concept of complexity and to demonstrate the value and possibilities of complexity science methods and tools for the future of burn care through examples from preclinical, clinical, and organizational perspective in burn care. The authors sincerely acknowledge the contribution of Jeroen G.N. van de Pauw Kraan, Titus R. Radstake, Ariette van Reekum, M.D. Ph.D., Prof. Marcel G.M. Olde Rikkert, M.D. Ph.D., Prof. Marinus de Kleuver, M.D. Ph.D., Lieke C. van Zuijlen, and Rosalyn Rus during the realization of this manuscript

The systemic and local immune response in burn patients is often extreme and derailed. As excessive inflammation can damage healthy tissues and slow down the healing process, modulation of inflammatory responses could limit complications and improve recovery. Due to its complexity, more detailed information on the immune effects of thermal injury is needed to improve patient outcomes. We therefore characterized and quantified subsets of immune cells and mediators present in human burn wound tissue (eschar), sampled at various time points. This study shows that after burn injury, the number of immune cells were persistently increased, unlike the normal wound healing process. There was an immediate, strong increase in neutrophils and a moderate increase in monocytes/macrophages and lymphocytes, especially in the second and third week post burn. The percentage of classical (CD14highCD16-) monocytes/macrophages demonstrated a steady decrease over time, whereas the proportion of intermediate (CD14highCD16+) monocytes/macrophages slowly increased. The absolute numbers of T cells, NK cells and B cells increased up to week 3, while the fraction of γδ T cells was increased only in week 1. Secretome profiling revealed high levels of chemokines and an overall pro-inflammatory cytokine milieu in burn tissue. The local burn immune response shows similarities to the systemic immune reaction, but differs in neutrophil maturity and lymphocyte composition. Altogether, the neutrophil surges, high levels of pro-inflammatory cytokines and limited immunosuppression might be key factors that prolong the inflammation phase and delay the wound healing process in burns.

Accurate assessment of burn wound depth and the associated healing potential is vital in determining the need for surgical treatment in burns. Infrared thermography measures the temperature of the burn wound noninvasively, thereby providing indirect information on its blood flow. Previous research demonstrated that a small, low-priced, handheld thermal imager has an excellent reliability, but a moderate validity for measuring burn wound healing potential. A new and more sensitive version of this convenient device has become available. The aim of this study was to evaluate the validity of thermography for measuring burn wound healing potential, compared to Laser Doppler Imaging (LDI) as a reference standard. Thermal images and LDI scans were obtained from burn wounds between 2 and 5 days postburn. Temperature differences between burned and nonburned skin (ΔT) were calculated. To evaluate validity, ΔT values were compared to the healing potential categories assessed by LDI. Two receiver operating characteristic curves were created and two ΔT cutoff values were calculated to illustrate the ability to discriminate between burn wounds that heal in a time period of less than 14 days, between 14 and 21 days, and more than 21 days. Between June and October 2018, 43 burn wounds in 32 patients were measured. ΔT cutoff values of 0.6°C (sensitivity 68%, specificity 95%) and −2.3°C (sensitivity 30%, specificity 95%) were calculated to discriminate between burn wounds that heal in 21 days, respectively. This study shows a good validity of the feasible thermal imager for the assessment of burn wound healing potential. Therefore, we consider it a promising technique to be used for triage in local hospitals and general practices, and as a valuable addition to clinical evaluation in burn centers.

Five years ago in this journal we described our research into 3D bioprinting of ear cartilage for the purpose of making personalized cartilage implants for facial reconstruction. 3D bioprinting makes it possible to place living cells in a biodegradable scaffold to give a 3D structure to the tissue. We are able to develop a hybrid auricular cartilage implant model. However, Long term in vivo experiments are needed to test preclinical applicability. Nevertheless, the work presented in our studies provides a potential strategy for the use of biofabricated tissue constructs in the clinic. In short, 3D bioprinting is still in its infancy and has no direct clinical application yet. Before the step to the clinic can be made, the technique still has to go through a preclinical phase in which it is investigated how the 3D printed tissue would appear in vivo.

To deal with permanent deformations and residual stresses, we consider a morphoelastic model for the scar formation as the result of wound healing after a skin trauma. Next to the mechanical components such as strain and displacements, the model accounts for biological constituents such as the concentration of signaling molecules, the cellular densities of fibroblasts and myofibroblasts, and the density of collagen. Here we present stability constraints for the one-dimensional counterpart of this morphoelastic model, for both the continuous and (semi-) discrete problem. We show that the truncation error between these eigenvalues associated with the continuous and semi-discrete problem is of order $${{\mathcal {O}}}(h^2)$$ O ( h 2 ) . Next we perform numerical validation to these constraints and provide a biological interpretation of the (in)stability. For the mechanical part of the model, the results show the components reach equilibria in a (non) monotonic way, depending on the value of the viscosity. The results show that the parameters of the chemical part of the model need to meet the stability constraint, depending on the decay rate of the signaling molecules, to avoid unrealistic results.

In burn patients, wound healing is often accompanied by hypertrophic scarring (HTS), resulting in both functional and aesthetic problems. HTSs are characterized by abundant presence of myofibroblasts (MFs) residing in the dermis. HTS development and MF persistence is primarily regulated by TGF-β signalling. A promising method to target the transforming growth factor receptor I (TGFβRI; also known as activin-like kinase 5 (ALK5)) is by making use of exon skipping through antisense oligonucleotides. In HTS the distinguishing border between the papillary dermis and the reticular dermis is completely abrogated, thus exhibiting a one layered dermis containing a heterogenous fibroblast population, consisting of papillary fibroblasts (PFs), reticular fibroblasts (RFs) and MFs. It has been proposed that PFs, as opposed to RFs, exhibit anti-fibrotic properties. Currently, it is still unclear which fibroblast subtype is most affected by exon skipping treatment. Therefore, the aim of this study was to investigate the effect of TGFβRI inhibition by exon skipping in PF, RF and HTS fibroblast monocultures. Morphological analyses revealed the presence of a PF-like population after exon skipping in the different fibroblast cultures. This observation was further confirmed by the expression of genes specific for PFs, demonstrated by qPCR analyses. Further investigations on mRNA and protein level revealed that indeed MFs and to a lesser extent RFs are targeted by exon skipping. Furthermore, collagen gel contraction analysis showed that ALK5 exon skipping reduced TGF-β- induced contraction together with decreased alpha-smooth muscle actin expression levels. In conclusion, we show for the first time that exon skipping primarily targets pro-fibrotic fibroblasts. This could be a promising step towards reduced HTS development of burn tissue.

We consider a one-dimensional morphoelastic model describing post-burn scar contraction. Contraction can lead to a limited range of motion (contracture). Reported prevalence of burn scar contractures are 58.6% at 3-6 weeks and 20.9% at 12 months post-reconstructive surgery after burns. This model describes the displacement of the dermal layer of the skin and the development of the effective Eulerian strain in the tissue. Besides these components, the model also contains components that play a major role in the skin repair after trauma. These components are signaling molecules, fibroblasts, myofibroblasts, and collagen. We perform a sensitivity analysis for many parameters of the model and use the results for a feasibility study. In this study, we test whether the model is suitable for predicting the extent of contraction in different age groups. To this end, we conduct an extensive literature review to find parameter values. From the sensitivity analysis, we conclude that the most sensitive parameters are the equilibrium collagen concentration in the dermal layer, the apoptosis rate of fibroblasts and myofibroblasts, and the secretion rate of signaling molecules. Further, although we can use the model to simulate significant distinct contraction densities in different age groups, our results differ from what is seen in the clinic. This particularly concerns children and elderly patients. In children we see more intense contractures if the burn injury occurs near a joint, because the growth induces extra forces on the tissue. Elderly patients seem to suffer less from contractures, possibly because of excess skin. The authors are grateful for the fnancial support by the Dutch Burns Foundation under Project 17.105. This project is funded by the Dutch Burns Foundation under Project 17.105.

Background: Burns induce a boost in local and systemic complement levels as well as immune cell infiltration in the burn wound, that may negatively affect wound healing. Objective: In this study, the effects of long-term treatment with complement inhibitor C1 esterase inhibitor (C1inh) on post-burn inflammation and wound healing parameters were analyzed in time up to 60 days post-burn. Method: Burned pigs were treated either with or without C1inh up to 15 days post-burn. Burn wound biopsies and blood were collected at different time points up to 60 days post-burn. Thereafter, complement in blood as well as complement and immune cells in the wound, capillary leakage, necrosis, reepithelialization and wound contraction were quantified. Results: No significant differences in complement C3 blood levels were observed at any time point between C1inh-treated and control pigs. In the wound, complement C4 levels were significantly lower in the C1inh group than in controls at day 3-6 and 21-30 post-burn. Similarly, C3 levels, neutrophil and macrophage infiltration in the wound were, although not statistically significant, reduced in C1inh-treated pigs at day 9-14 post-burn. No differences in lymphocyte infiltration in the wound were found between C1inh and control pigs. C1inh-treated pigs also showed reduced capillary leakage. Despite these effects, no significant differences in the long-term wound healing parameters necrosis, reepithelialization and wound contraction were observed between C1inh and control pigs. Conclusion:: In pigs 15 days of C1inh treatment after burn, leads to a reduction in local inflammation and capillary leakage in the burn wound without affecting long-term wound healing parameters.

Three-dimensional (3D) bioprinting of patient-specific auricular cartilage constructs could aid in the reconstruction process of traumatically injured or congenitally deformed ear cartilage. To achieve this, a hydrogel-based bioink is required that recapitulates the complex cartilage microenvironment. Tissue-derived decellularized extracellular matrix (dECM)-based hydrogels have been used as bioinks for cell-based 3D bioprinting because they contain tissue-specific ECM components that play a vital role in cell adhesion, growth, and differentiation. In this study, porcine auricular cartilage tissues were isolated and decellularized, and the decellularized cartilage tissues were characterized by histology, biochemical assay, and proteomics. This cartilage-derived dECM (cdECM) was subsequently processed into a photo-crosslinkable hydrogel using methacrylation (cdECMMA) and mixed with chondrocytes to create a printable bioink. The rheological properties, printability, and in vitro biological properties of the cdECMMA bioink were examined. The results showed cdECM was obtained with complete removal of cellular components while preserving major ECM proteins. After methacrylation, the cdECMMA bioinks were printed in anatomical ear shape and exhibited adequate mechanical properties and structural integrity. Specifically, auricular chondrocytes in the printed cdECMMA hydrogel constructs maintained their viability and proliferation capacity and eventually produced cartilage ECM components, including collagen and glycosaminoglycans (GAGs). The potential of cell-based bioprinting using this cartilage-specific dECMMA bioink is demonstrated as an alternative option for auricular cartilage reconstruction.

The treatment of burn wounds by enzymatic debridement using bromelain has shown promising results in our burn center. However, inadequate debridement occurred in a few cases in which the etiology of the burn was attributed to relatively low temperature burns. We hypothesized that bromelain is ineffective in burns in which collagen denaturation, which occurs approximately at 65°C, has not taken place. Our objective was to assess whether there is a relationship between the denaturation of collagen and the ability of bromelain to debride acute scald burn wounds of different temperatures. Ex vivo human skin from four different donors was cut into 1x1 cm samples, and scald burns were produced by immersion in water at temperatures of 40°C, 50°C, 60°C, 70°C, and 100°C for 20 minutes. Denaturation of collagen was assessed with histology, using hematoxylin and eosin (H&E) staining and a fluorescently labeled collagen hybridizing peptide (CHP), and with second harmonic generation (SHG) microscopy. Burned samples and one control sample (room temperature) were weighed before and after application of enzymatic debridement to assess the efficacy of enzymatic debridement. After enzymatic debridement, a weight reduction of 80% was seen in the samples heated to 70°C and 100°C, whereas the other samples showed a reduction of 20%. Unfolding of collagen, loss of basket-weave arrangement, and necrosis was seen in samples heated to 60°C or higher. Evident CHP fluorescence, indicative of collagen denaturation, was seen in samples of 60°C, 70°C and 100°C. SHG intensity, signifying intact collagen, was significantly lower in the 70°C and 100°C group (P '.05) compared to the lower temperatures. In conclusion, denaturation of collagen in skin samples occurred between 60°C and 70°C and strongly correlated with the efficacy of enzymatic debridement. Therefore, enzymatic debridement with the use of bromelain is ineffective in scald burns lower than 60°C.

We consider a morphoelastic framework that models permanent deformations. The text treats a stability assessment in one dimension and a preservation of symmetry in multiple dimensions. Next, we treat the influence of uncertainty in some of the field variables onto the predicted behaviour of tissue.

Purpose Reliable and valid assessment of burn wound depth or healing potential is essential to treatment decision-making, to provide a prognosis, and to compare studies evaluating different treatment modalities. The aim of this review was to critically appraise, compare and summarize the quality of relevant measurement properties of techniques that aim to assess burn wound depth or healing potential. Methods A systematic literature search was performed using PubMed, EMBASE and Cochrane Library. Two reviewers independently evaluated the methodological quality of included articles using an adapted version of the Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A synthesis of evidence was performed to rate the measurement properties for each technique and to draw an overall conclusion on quality of the techniques. Results Thirty-six articles were included, evaluating various techniques, classified as (1) laser Doppler techniques; (2) thermography or thermal imaging; (3) other measurement techniques. Strong evidence was found for adequate construct validity of laser Doppler imaging (LDI). Moderate evidence was found for adequate construct validity of thermography, videomicroscopy, and spatial frequency domain imaging (SFDI). Only two studies reported on the measurement property reliability. Furthermore, considerable variation was observed among comparator instruments. Conclusions Considering the evidence available, it appears that LDI is currently the most favorable technique; thereby assessing burn wound healing potential. Additional research is needed into thermography, videomicroscopy, and SFDI to evaluate their full potential. Future studies should focus on reliability and measurement error, and provide a precise description of which construct is aimed to measure.

Background: In burn patients, wound healing is often accompanied by hypertrophic scar (HS) development, resulting in both functional and aesthetic problems. HSs are characterised by abundant presence of myofibroblasts that contribute to overproduction of extracellular matrix (ECM) that is regulated by the TGF-β signalling pathway. Studies have shown that inhibition of TGF-β receptors in fibrotic diseases reduces the fibrotic load. In the present study, we aim to inactivate ALK5, also known as TGF-β receptor I, in human HS fibroblasts by exon skipping using antisense oligonucleotides (AONs). Methods: HS biopsies were used to isolate and set up fibroblast monocultures. AONs targeting ALK5 were supplemented to the fibroblast cultures to induce exon skipping, while pharmacological ALK5 inhibition was induced using SB431542. AON delivery in HS fibroblasts was examined using immunofluorescence (IF), while TGF-β signalling downstream targets, such as Smad2/3, PAI-1, ACTA2, COL1A1 and COL3A1, were analysed using touchdown polymerase chain reaction (PCR), quantitative PCR (qPCR), IF or western blotting. Results: Our data clearly demonstrate that AONs were successfully delivered in the nuclei of HS fibroblasts and that functional exon skipping of ALK5 took place as confirmed with touchdown PCR and qPCR. In addition, exon skipping affected the expression of ECM-related genes, such as type I/III collagens, PAI-1 and CCN2. Moreover, AON treatment did not affect the migration of HS fibroblasts in a model for wound healing. Conclusion: Exon skipping is a promising tool to modulate the TGF-β signalling pathway in HS. This would open a therapeutic window for the treatment of patients suffering from HSs., Lay Summary In this research article, we describe the effect of exon skipping, a type of gene therapy, on fibroblasts that were isolated from hypertrophic scar biopsies. In these fibroblasts, we targeted the overactivated molecular pathway involved in the development of hypertrophic scars. Furthermore, this approach has been successfully studied in different diseases that show the same overactive molecular pathway. It is therefore of great interest to assess the effects of exon skipping in hypertrophic scars. The biopsies were retrieved from excisions performed on patients that developed post-burn hypertrophic scars. Upon arrival, the hypertrophic scar biopsies were prepared and the fibroblasts were isolated and put in culture on a Petri dish. All treatments were then added to the culture medium of the fibroblasts. In this study, we found that exon skipping was able to affect the main molecular pathway that is involved in the development of hypertrophic scars. Further, since this specific molecular pathway is of great importance in normal wound healing, we determined the effect of exon skipping on the migration of these fibroblasts. By simulating wound healing in a so-called scratch assay, we found that exon skipping does not affect fibroblast migration. Altogether, the present study shows that exon skipping has great potential as a novel treatment option in the management of hypertrophic scars. Additional research is warranted before we can start clinical trials.

Millions of women worldwide have silicone breast implants. It has been reported that implant failure occurs in approximately a tenth of patients within 10 years, and the consequences of dissemination of silicone debris are poorly understood. Currently, silicone detection in histopathological slides is based on morphological features as no specific immunohistochemical technique is available. Here, we show the feasibility and sensitivity of stimulated Raman scattering (SRS) imaging to specifically detect silicone material in stained histopathological slides, without additional sample treatment. Histology slides of four periprosthetic capsules from different implant types were obtained after explantation, as well as an enlarged axillary lymph node from a patient with a ruptured implant. SRS images coregistered with bright-field images revealed the distribution and quantity of silicone material in the tissue. Fast and high-resolution imaging of histology slides with molecular specificity using SRS provides an opportunity to investigate the role of silicone debris in the pathophysiology of implant-linked diseases.

Au cours des dernieres decennies, l’evaluation des resultats d’un traitement medical est devenue de plus en plus importante. La medecine fondee sur les preuves necessite que le domaine de recherche evalue l’efficacite des traitements nouveaux et existants. Dans cet article, nous nous concentrons sur la peau et les cicatrices et nous donnons un bref apercu des exigences clinimetriques et des echelles de cicatrices frequemment utilisees – en particulier l’echelle patient and observer scar assessment scale (POSAS) que l’on peut traduire en francais par “echelle d’evaluation des cicatrices patient et observateur” (EECPO).

Summary Background The ischial region is the site most affected by pressure sores and has the highest recurrence and complication rates compared to other affected sites. We developed a practical and safe pedicled flap for reconstruction of ischial pressure sores based on the rich available perforators from the internal pudendal artery and the surplus of skin at the infragluteal fold. Methods A retrospective cohort study was conducted in all patients who underwent ischial pressure ulcer reconstruction using the PIPAP flap between March 2010 and March 2017. The skin flap was designed along the gluteal fold. The skin perforators of the pudendal artery were marked with a Doppler probe in the medial region of the gluteal fold. Surgery was performed in the jackknife position, and flaps were elevated in the suprafascial plane. Patients were assessed for minor (requiring no additional surgery) and major complications (requiring additional surgery). Results Twenty-seven patients (34 flaps) were identified. The median follow-up period was 38 months (IQR 37). Primary closure of the donor-site was achieved in all procedures, only one flap required muscle flap transposition in order to fill the dead space. The mean operating time was 60 ± 21 minutes. In six flaps (9%) wound healing problems were noted that did not require an additional operative procedure. Among the nine flaps (27%) that required a second procedure, 3 (9%) were necessary due to recurrent ulcers. Conclusions The PIPAP flap is a safe and reliable alternative for ischial pressure sore reconstruction, certainly when compared to available techniques. Moreover, it has significant advantages over other techniques including minimal donor-site morbidity, preservation of posterior thigh skin, buttock-line integrity and reliable vascularity.

Obtaining adequate information on scar characteristics is important for monitoring their evolution and the effectiveness of clinical treatment. The aberrant type of collagen in scars may give rise to specific birefringent properties, which can be determined using polarization-sensitive optical coherence tomography (PS-OCT). The aim of this pilot study was to evaluate a method to quantify the birefringence of the scanned volume and correlate it with the collagen density as measured from histological slides. Five human burn scars were measured in vivo using a handheld probe and custom-made PS-OCT system. The local retardation caused by the tissue birefringence was extracted using the Jones formalism. To compare the samples, histograms of birefringence values of each volume were produced. After imaging, punch biopsies were harvested from the scar area of interest and sent in for histological evaluation using Herovici polychrome staining. Two-dimensional en face maps showed higher birefringence in scars compared to healthy skin. The Pearson's correlation coefficient for the collagen density as measured by histology versus the measured birefringence was calculated at r = 0.80 (p = 0.105). In conclusion, the custom-made PS-OCT system was capable of in vivo imaging and quantifying the birefringence of human burn scars, and a nonsignificant correlation between PS-OCT birefringence and histological collagen density was found.

Burn-induced tissue loss is partly related to secondary expansion of necrosis into vital dermis neighboring the initial burn injury. An important factor herein is the severe loss of perfusion of the burn wound, probably caused by microvascular damage induced by the intense local inflammatory responses as well as burn-induced hypercoagulation. We hypothesize that the formation of neutrophilic extracellular traps (NETs) play an important role in this. The purpose of this study was to investigate postburn intravascular thrombosis, NETs formation and the coagulant state in the microvasculature of burns in both animal models and patients. We used two in vivo burn wound models: rats and pigs. In rats, the entire wound was excised at day 14 postburn and in pigs burn wound biopsies were collected at different time points up to 60 days postburn. To confirm the data in patients, eschar from the burn wound was obtained from burn wound patients at different time points after wounding. The number of intravascular thrombi, the presence of intravascular NETs and the number of tissue factor (TF) positive blood vessels in the burn wound was determined. In rats, a significant increase in intravascular thrombi and TF expression was observed 14 days postburn, that in majority coincided with NETs. In pigs, a significant increase in intravascular thrombi and TF expression was found over time up to 60 days postburn, that in majority coincided with NETs too. Also in eschar of burn wound patients, a significant increase in intravascular thrombi was noted, that in majority coincided with NETs, already 0.5 days postburn and remained elevated up to 46 days postburn. This study shows the presence of NETosis in microcirculatory thrombosis of burn wounds and a switch in the microcirculatory endothelium toward a procoagulant phenotype.

Following severe injury, not just the skin but also the subcutis may be destroyed. Consequently, the developing scar can become adherent to underlying structures. Reconstruction of the subcutis can be achieved by autologous fat grafting. Our aim was to evaluate the long-term scar outcome after single-treatment autologous fat grafting using a comprehensive scar evaluation protocol. Scar assessment was performed preoperatively in 40 patients. A 12-month follow-up assessment was performed in 36 patients, using the Cutometer, the Patient and Observer Scar Assessment Scale, and DSM II ColorMeter. The Cutometer parameters elasticity and maximal extension improved with 28 and 22% (both p

The evaluation of scar treatment benefits from exact structural measurements. Accurate assessment of thickness, surface area, and relief is crucial in routine clinical follow-up. From an experimental perspective, precise visualization of the microstructural organization is necessary for a better understanding of the mechanisms underlying pathological scarring. Structural proteins in scars differ from healthy skin in terms of amount, type, and importantly, organization. The precise quantification of this extracellular matrix (ECM) organization was, until recently, limited to two-dimensional images from fixated and stained tissue. Advances in optical techniques now allow high-resolution imaging of these structures, in some cases in vivo. The enormous potential of these techniques as objective assessment tools is illustrated by a substantial increase in available devices. This chapter describes currently used devices and techniques used in the clinical follow-up of scar progression from a volumetric standpoint. Furthermore, some of the most powerful techniques for microstructural research are described including optical coherence tomography, nonlinear optical techniques such as second harmonic generation microscopy, and confocal microscopy.

This chapter provides an overview of the epidemiology, pathophysiology, course, measurement, and potential therapies for pigmentation disorders in scars. Pigmentation problems are a common consequence of deep partial- and full-thickness burns, other skin trauma or disease, and surgical procedures. Both hypopigmentation and hyperpigmentation can cause esthetic and psychological issues, which may influence quality of life. The role of melanocytes and the maturation of pigmentation problems are discussed. To determine the severity of pigmentation problems and for therapeutic evaluation, different subjective and objective methods have been validated. Simple and easy-to-use measurement instruments are available based on spectrophotometric techniques. Also scar assessment scales with subscales for color and pigmentation are convenient and validated methods for quantitative evaluation of skin pigment disorders. Treatment options are discussed and include camouflage therapy, topical treatments, chemical peels, laser therapy, dermatography, dermabrasion, microneedling, skin grafting, cell therapy, and excision. It is advised to first try the conservative options and to dose and monitor the treatment to prevent overshoot and complications.

Over the last decades, many scar assessment scales have been developed, not only to evaluate the effectiveness of new and existing treatments in the research setting but also to monitor scars in individual patients. Clinician-reported scar scales allow for the evaluation of observable aspects of the scar, while patient-reported scar scales enable the evaluation of additional health domains that cannot be observed by clinicians, such as scar symptoms or sensations and quality of life. The quality of scar assessment scales is determined by several measurement properties (i.e., validity, reliability, and responsiveness). This chapter provides an overview of the content and development of the most frequently used scar assessment scales.

Reepithelialization is crucial for effective wound repair in burn wounds. Reactive oxygen species (ROS) have shown to be important in this. Recent studies suggest that NOX proteins produce ROS in keratinocytes. In the present study, we have studied NOX proteins in burn wounds, including the effect of C1-esterase inhibitor (C1inh) hereon, which is the endogenous inhibitor of complement activity whereof we have shown previously that it also increased the rate of reepithelialization in burn wounds. Skin tissue derived from healthy control Wistar rats (n = 6) were compared with burn-injured rats, with (n = 7) or without C1inh treatment (n = 7). After 14 days, rats were terminated. From the burn-injured rats, the entire wound and nonburned skin from the hind leg, that is, internal control was excised. From the control rats, dorsal skin was excised. In these skin samples, NOX2 and NOX4 were analyzed immunohistochemically. In nonburned rats, NOX2 was found in keratinocytes in both the basal layer and suprabasal layer of the epidermis; and the number of NOX2-positive keratinocytes was 367/mm2 (254–378). In burned rats, the number of NOX2-positive keratinocytes was significantly increased in the newly forming epidermis in the burned area to 1019/mm2 (649–1172), especially in the suprabasal layer, but significantly decreased in remote nonburned skin to 22/mm2 (6–89). C1inh treatment counteracted these changes in epidermal NOX2 expression in burned rats, both in the burned area as in remote nonburned skin. No NOX4 expression was found in the epidermis in none of the groups. NOX2 expression was increased in keratinocytes in newly forming epidermis after burn injury. C1inh, a drug that increases the rate of reepithelialization, counteracted this effect. These results suggest a role for NOX2 in the reepithelialization of burn wounds.

Complexity of patient care is rapidly increasing as a consequence of rising numbers of patients with complex multimorbidity. Not just the patient as a whole, but also the networks of organs, tissues and cells are forming a complex adaptive system (CAS). A CAS is defined as a network of several components ('agents') with lots of mutual feedback loops between which there are circular causalities; the predictability of a CAS is limited by definition. However, current guidelines and evidence-based medicine assume that diseases and the medical interventions to address them are predictable. Physicians' brains are complex neural networks that are much better at dealing with complex situations than guidelines. In the near future, physicians will also get help from advanced computer simulation models that make better diagnostic analyses on the basis of detailed phenotyping and are more accurate when predicting possible courses of disease and treatment outcomes.