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Background Chronic non-healing wounds present a substantial economic burden to healthcare system; significant reductions in quality of life for those affected, and precede often serious events such as limp amputations or even premature deaths. This burden is also likely to increase with a larger proportion of elderly and increasing prevalence of life-style diseases such as obesity and diabetes. Reviews of the evidence on the burden of illness associated with chronic wounds have not been comprehensive in scope and have not provided an assessment of the distribution of the health care costs across categories of resource use. Methods/design This study is a systematic review of multiple databases for studies on adult patients with chronic wounds and with the primary objective to assess the impact on health-related quality of life by category of ulcers, and associated direct and indirect costs. Eligible studies will primary be empirical studies evaluating, describing or comparing measurement of quality of life and economic impact. Two reviewers will independently screen titles and abstracts and select studies involving adults with chronic wounds. These investigators will also independently extract data using a pre-designed data extraction form. Differences in applied methodologies and uncertainties will clearly be accounted for. Conservative valuations of costs and impact on health-related quality of life will be prioritised. Variations that may depend on age distribution, the categorisation of ulcer, healthcare system etc. will be described clearly. Discussion The proposed systematic review will yield a comprehensive assessment of the humanistic and economic burden of chronic wounds in an adult population. A better understanding of the humanistic and economic burden of chronic wounds is essential for policy and planning purposes, to monitor trends in disease burden and not at least in order to estimate the real-world cost-effectiveness of new treatments and therapies. Systematic review registration PROSPERO CRD42016037496

Background Chronic wounds impose a significant and often underappreciated burden to the individual, the healthcare system and the society as a whole. Preliminary literature search suggests that there are at present no reliable estimates on the total prevalence of chronic wounds for different settings and categories of chronic wounds. Such information is essential for policy and planning purposes as the increasing number of elderly and the prevalence of lifestyle diseases point in the direction of an increased burden. Knowledge about the prevalence and incidence of chronic wounds in relation to population characteristics is important for informing healthcare planning and resource allocation. The objective is to present a transparent process for how to review the existing literature on the prevalence and incidence rates of chronic wounds and resulting implications. Methods/design We will search electronic bibliographic databases (MEDLINE, EMBASE, the EBM Reviews and Cochrane, Cumulative Index to Nursing and allied Health Literature (CINAHL), PsycINFO, Global Health) and reference lists of included articles. Two investigators will independently screen titles and abstracts and select studies involving adults with chronic wounds. These investigators will also independently extract data using a pre-designed data extraction form that will cover information on demographics, diagnostics including disease prevalence, medical history, hospital and community-based management and outcomes. Subgroup analysis and sensitivity analysis will be performed to address the heterogeneity across studies. Meta-analysis will also be performed if homogeneous group of studies will be found. The collective evidence will be further stratified according to the important background variables if allowed. Discussion This study will describe the available epidemiological evidence and summarise prevalence and incidence rates of chronic wounds and related complications. A better understanding of the relationship between population profile and the prevalence of chronic wounds and related complications will be helpful in the development of guidelines for patient management. Systematic review registration PROSPERO CRD42016037355

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by an impaired epidermal barrier, dysregulation of innate and adaptive immunity, and a high susceptibility to bacterial colonization and infection. In the present study, bacterial biofilm was visualized by electron microscopy at the surface of AD skin. Correspondingly, Staphylococcus aureus ( S . aureus ) isolates from lesional skin of patients with AD, produced a substantial amount of biofilm in vitro . S . aureus biofilms showed less susceptibility to killing by the antimicrobial peptide LL-37 when compared with results obtained using planktonic cells. Confocal microscopy analysis showed that LL-37 binds to the S . aureus biofilms. Immuno-gold staining of S . aureus biofilm of AD skin detected the S . aureus derived protease staphopain adjacent to the bacteria. In vitro , staphopain B degraded LL-37 into shorter peptide fragments. Further, LL-37 significantly inhibited S . aureus biofilm formation, but no such effects were observed for the degradation products. The data presented here provide novel information on staphopains present in S . aureus biofilms in vivo , and illustrate the complex interplay between biofilm and LL-37 in skin of AD patients, possibly leading to a disturbed host defense, which facilitates bacterial persistence.

Recent advances in mass spectrometry-based peptidomics have catalyzed the identification and quantification of thousands of endogenous peptides across diverse biological systems. However, the vast peptidomic landscape generated by proteolytic processing poses several challenges for downstream analyses and limits the comparability of clinical samples. Here, we present an algorithm that aggregates peptides into peptide clusters, reducing the dimensionality of peptidomics data, improving the definition of protease cut sites, enhancing inter-sample comparability, and enabling the implementation of large-scale data analysis methods akin to those employed in other omics fields. We showcase the algorithm by performing large-scale quantitative analysis of wound fluid peptidomes of highly defined porcine wound infections and human clinical non-healing wounds. This revealed signature phenotype-specific peptide regions and proteolytic activity at the earliest stages of bacterial colonization. We validated the method on the urinary peptidome of type 1 diabetics which revealed potential subgroups and improved classification accuracy. Studies of protein degradation through peptidomic analyses are complicated by the vast potential peptidomic landscapes. Here, the authors present a method that cluster peptides, simplifying down-stream analyses and apply it identify pathogen-specific peptide patterns in infected wounds.

Thrombin-derived C-terminal peptides (TCPs) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed interaction between TCPs and human CD14. Further, we show that TCPs bind to the LPS-binding hydrophobic pocket of CD14 and identify the peptide region crucial for TCP interaction with LPS and CD14. Taken together, our results demonstrate the role of structural transitions in LPS complex formation and CD14 interaction, providing a molecular explanation for the previously observed therapeutic effects of TCPs in experimental models of bacterial sepsis and endotoxin shock. Thrombin-derived C-terminal peptides (TCPs) have anti-endotoxic functions in wounds by binding to bacterial lipopolysaccharide (LPS) and Gram-negative bacteria. Here authors use a spectrum of biophysical techniques to determine the conformation of a TCP in complex with LPS and define the interaction between TCPs and CD14.

Neutrophil extracellular traps (NETs) consist of a decondensed DNA scaffold decorated with neutrophil-derived proteins. The proteome of NETs, or \"NETome,\" has been largely elucidated . However, components such as plasma and extracellular matrix proteins may affect the NETome under physiological conditions. Here, using a reductionistic approach, we explored the effects of two proteases active during injury and wounding, human thrombin and plasmin, on the NETome. Using high-resolution mass spectrometry, we identified a total of 164 proteins, including those previously not described in NETs. The serine proteases, particularly thrombin, were also found to interact with DNA and bound to NETs . Among the most abundant proteins were those identified previously, including histones, neutrophil elastase, and antimicrobial proteins. We observed reduced histone (H2B, H3, and H4) and neutrophil elastase levels upon the addition of the two proteases. Analyses of NET-derived tryptic peptides identified subtle changes upon protease treatments. Our results provide evidence that exogenous proteases, present during wounding and inflammation, influence the NETome. Taken together, regulation of NETs and their proteins under different physiological conditions may affect their roles in infection, inflammation, and the host response.

The normal wound healing process is characterised by proteolytic events, whereas infection results in dysfunctional activations by endogenous and bacterial proteases. Peptides, downstream reporters of these proteolytic actions, could therefore serve as a promising tool for diagnosis of wounds. Using mass-spectrometry analyses, we here for the first time characterise the peptidome of human wound fluids. Sterile post-surgical wound fluids were found to contain a high degree of peptides in comparison to human plasma. Analyses of the peptidome from uninfected healing wounds and Staphylococcus aureus -infected wounds identify unique peptide patterns of various proteins, including coagulation and complement factors, proteases, and antiproteinases. Together, the work defines a workflow for analysis of peptides derived from wound fluids and demonstrates a proof-of-concept that such fluids can be used for analysis of qualitative differences of peptide patterns from larger patient cohorts, providing potential biomarkers for wound healing and infection. Infected wounds and burns represent a serious risk to patients: they can delay healing and, if left untreated, can lead to generalised infection or sepsis, organ failure and death. Wounds and burns get infected when harmful micro-organisms, such as bacteria, enter the wound. Predicting the risk of infections, and detecting them early, could reduce their impact and make treating them easier. A way to distinguish between healing and infected wounds is to study how proteins are broken down in each situation. Proteases are the enzymes that break down proteins, and they are different in healing wounds and infected wounds that are failing to heal. This is because, while the body produces proteases, the bacteria that cause infection do so too. Each protease breaks down proteins in a specific way, resulting in a different set of protein fragments, known as peptides. Together, all the peptides in a wound are referred to as the wound’s ‘peptidome’. Studying the peptidome of a wound could show whether it is infected, and even what type of bacteria might be responsible, which could help identify suitable treatments. Van der Plas et al. used a technique called mass spectrometry to study the peptidome of wounds after surgery. Sterile post-surgical wounds showed high levels of peptides compared to plasma, the liquid component of blood, with up to 4,300 different peptides. Comparing healing wounds to ones infected with the bacterium Staphylococcus aureus revealed that infected wounds contained peptides from about 150 proteins not found in uninfected wounds, while peptides from 90 proteins were unique to uninfected wounds. The peptides exclusive to uninfected wounds included some linked to antimicrobial activity and immune system activity. Van der Plas et al.’s results suggest that analysing the peptidome may be an approach to tracking the healing status of wounds, making it easier to detect infection before symptoms are apparent. The next step will be to study more wounds and identify the reliable peptide markers to use them for diagnostic tests.

Human hair is laminar-fibrous tissue and an evolutionarily old keratinization product of follicle trichocytes. Studies on the hair proteome can give new insights into hair function and lead to the development of novel biomarkers for hair in health and disease. Human hair proteins were extracted by detergent and detergent-free techniques. We adopted a shotgun proteomics approach, which demonstrated a large extractability and variety of hair proteins after detergent extraction. We found an enrichment of keratin, keratin-associated proteins (KAPs), and intermediate filament proteins, which were part of protein networks associated with response to stress, innate immunity, epidermis development, and the hair cycle. Our analysis also revealed a significant deamidation of keratin type I and II, and KAPs. The hair shafts were found to contain several types of histones, which are well known to exert antimicrobial activity. Analysis of the hair proteome, particularly its composition, protein abundances, deamidated hair proteins, and modification sites, may offer a novel approach to explore potential biomarkers of hair health quality, hair diseases, and aging.

Background Despite the high morbidity and severe consequences of epidermolysis bullosa (EB), current treatments remain inadequate, lacking efficacy and the ability to target the microbial and inflammatory components of EB wounds. In this first-in-human open-label, single-arm study—part 3 of a 3-part Phase 1 clinical trial—we examined the safety, tolerability, and systemic exposure of topically applied TCP-25, a thrombin-derived C-terminal peptide with demonstrated anti-inflammatory, antimicrobial, and wound-healing properties in murine and porcine infection models. Results Five patients with inherited recessive dystrophic EB received TCP-25 gel, applied to a 50-cm 2 primary wound treatment area, which was compared with a reference wound treatment area which received standard wound care alone. TCP-25 gel was also applied to a 50-cm 2 secondary wound treatment area of a higher age or in a more complicated area. TCP-25 gel was administered at escalating doses of 7.25 mg, 14.5 mg, 21.5 mg, and 43.0 mg, 3 times per week over 4 consecutive 1-week treatment periods. For the primary safety endpoint, 11 adverse events were recorded, 10 unlikely related to treatment and mild or moderate in severity, with one possibly linked to gel adhesion. Additionally, no abnormal local reactions were observed in any wound treated with TCP-25, nor in any reference wound, compared to expected wound healing outcomes. For the secondary endpoint, we did not observe any systemic plasma uptake of TCP-25 in any participant. In an exploratory analysis, we observed a steady reduction in open wound size in TCP-25-treated primary wounds, culminating in a median reduction of 76% from baseline to Day 29. Reference wounds exhibited variable changes in wound size, including some increases in size at earlier time points. Secondary wounds that were treated with TCP-25 also decreased steadily, reaching a median open wound size reduction of 78% on day 29. Additionally, TCP-25 demonstrated potential efficacy in accelerating wound healing. Conclusions Topical TCP-25 gel was safe and well tolerated and showed no systemic uptake in patients with dystrophic EB, demonstrating promising effects on wound healing. Trial Registration Clinical trial NCT05378997 was registered 2022–05-12 ( https://clinicaltrials.gov/study/NCT05378997 ) and amended 2024–02-12 to include Part-3 on dystrophic EB. The amendment was prospectively registered at EudraCT (2021-004728-14).

Pseudomonas aeruginosa is an opportunistic pathogen known for its immune evasive abilities amongst others by degradation of a large variety of host proteins. Here we show that digestion of thrombin by P. aeruginosa elastase leads to the release of the C-terminal thrombin-derived peptide FYT21, which inhibits pro-inflammatory responses to several pathogen-associated molecular patterns in vitro and in vivo by preventing toll-like receptor dimerization and subsequent activation of down-stream signalling pathways. Thus, P. aeruginosa ‘hijacks’ an endogenous anti-inflammatory peptide-based mechanism, thereby enabling modulation and circumvention of host responses. Neutrophil elastase cleaves thrombin generating anti-inflammatory peptides. Here the authors show that cleavage of thrombin by Pseudomonas aeruginosa elastase generates a peptide that prevents TLR dimerization and signaling, interfering with the inflammatory response to avoid host defense.