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.
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Long‐term outcome of burn scars as well as the relation with clinically relevant parameters has not been studied quantitatively. Therefore, we conducted a detailed analysis on the clinical changes of ...burn scars in a longitudinal setup. In addition, we focused on the differences in scar quality in relation to the depth, etiology of the burn wound and age of the patient. Burn scars of 474 patients were subjected to a scar assessment protocol 3, 6, and 12 months postburn. Three different age groups were defined (≤5, 5–18, and ≥18 years). The observer part of the Patient and Observer Scar Assessment Scale revealed a significant (p < 0.001) improvement in scar quality at 12 months compared with the 3‐ and 6‐month data. Predictors for severe scarring are depth of the wound (p < 0.001) and total body surface area burned (p < 0.001). Etiology (p = 0.753) and age (p > 0.230) have no significant influence on scar quality when corrected for sex, total body surface area burned, time, and age or etiology, respectively.
Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and ...reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, which generally heals faster compared to skin. Several studies have identified differences between oral and skin wound healing. Most of these studies however focus only on a single stage of wound healing or a single cell type. The aim of this review is to provide an extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic properties of resident cells and differential expression of cytokines and growth factors, multiple external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased extracellular matrix remodeling all contribute to the superior wound healing and reduced scar formation in oral mucosa, compared to skin.
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.
Severe burn injury causes local and systemic immune responses that can persist up to months, and can lead to systemic inflammatory response syndrome, organ damage and long-term sequalae such as ...hypertrophic scarring. To prevent these pathological conditions, a better understanding of the underlying mechanisms is essential. In this longitudinal study, we analyzed the temporal peripheral blood immune profile of 20 burn wound patients admitted to the intensive care by flow cytometry and secretome profiling, and compared this to data from 20 healthy subjects. The patient cohort showed signs of systemic inflammation and persistently high levels of pro-inflammatory soluble mediators, such as IL-6, IL-8, MCP-1, MIP-1β, and MIP-3α, were measured. Using both unsupervised and supervised flow cytometry techniques, we observed a continuous release of neutrophils and monocytes into the blood for at least 39 days. Increased numbers of immature neutrophils were present in peripheral blood in the first three weeks after injury (0.1-2.8 × 10
/ml after burn vs. 5 × 10
/ml in healthy controls). Total lymphocyte numbers did not increase, but numbers of effector T cells as well as regulatory T cells were increased from the second week onward. Within the CD4
T cell population, elevated numbers of CCR4
CCR6
and CCR4
CCR6
cells were found. Altogether, these data reveal that severe burn injury induced a persistent innate inflammatory response, including a release of immature neutrophils, and shifts in the T cell composition toward an overall more pro-inflammatory phenotype, thereby continuing systemic inflammation and increasing the risk of secondary complications.
Loss of perfusion in the burn wound might cause wound deepening and impaired healing. We previously showed persistent microvascular thrombosis coinciding with intraluminal neutrophils extracellular ...traps in human burned skin. This study investigates the presence of intraluminal citrullinated histone 3 (H3cit) from different cellular origins (neutrophils, monocytes, and lymphocytes) in relation to microvascular thrombosis of burn wounds. Eschar was obtained from burn patients (n = 18) 6–40 days postburn with a mean total burned body surface area of 23%. Microvascular presence of tissue factor (TF), factor XII (FXII) and thrombi was assessed by immunohistochemistry. Intramicrovascular cell death was analyzed via immunofluorescent microscopy, combining antibodies for neutrophils (MPO), monocytes (CD14), and lymphocytes (CD45) with endothelial cell markers CD31 and H3cit. Significantly increased microvascular expression of TF, FXII, and thrombi (CD31+) was found in all eschar samples compared with control uninjured skin. Release of H3cit from different cellular origins was observed in the lumen of the dermal microvasculature in the eschar tissue 7–40 days postburn, with release from neutrophilic origin being 2.7 times more abundant. Intraluminal presence of extracellular H3cit colocalizing with either MPO, CD14, or CD45 is correlated to increased microvascular thrombosis in eschar of burn patients.
Persistent microvascular thrombosis in burn wounds characterized by increased TF and FXII coincides with extracellular citrullinated histone 3 originated from neutrophils, monocytes, and lymphocytes. This data may provide new targets for the treatment of microvascular thrombosis and burn wound deepening.
For deep partial-thickness burns no consensus on the optimal treatment has been reached due to conflicting study outcomes with low quality evidence. Treatment options in high- and middle-income ...countries include conservative treatment with delayed excision and grafting if needed; and early excision and grafting. The majority of timing of surgery studies focus on survival rather than on quality of life. This study protocol describes a study that aims to compare long-term scar quality, clinical outcomes, and patient-reported outcomes between the treatment options. A multicentre prospective study will be conducted in the three Dutch burn centres (Rotterdam, Beverwijk, and Groningen). All adult patients with acute deep-partial thickness burns, based on healing potential with Laser Doppler Imaging, are eligible for inclusion. During a nine-month baseline period, standard practice will be monitored. This includes conservative treatment with dressings and topical agents, and excision and grafting of residual defects if needed 14-21 days post-burn. The subsequent nine months, early surgery is advocated, involving excision and grafting in the first week to ten days post-burn. The primary outcome compared between the two groups is long-term scar quality assessed by the Patient and Observer Scar Assessment Scale 3.0 twelve months after discharge. Secondary outcomes include clinical outcomes and patient-reported outcomes like quality of life and return to work. The aim of the study is to assess long-term scar quality in deep partial-thickness burns after conservative treatment with delayed excision and grafting if needed, compared to early excision and grafting. Adding to the ongoing debate on the optimal treatment of these burns. The broad range of studied outcomes will be used for the development of a decision aid for deep partial-thickness burns, to fully inform patients at the point of consent to surgery and support optimal person-centred care.
Burn injury induces a complex inflammatory response, both locally and systemically, and is not yet completely unravelled and understood. In order to enable the development of accurate treatment ...options, it is of paramount importance to fully understand post-burn immunology. Research in the last decades describes insights into the prolonged and excessive inflammatory response that could exist after both severe and milder burn trauma and that this response differs from that of none-burn acute trauma. Persistent activity of complement, acute phase proteins and pro- and anti-inflammatory mediators, changes in lymphocyte activity, activation of the stress response and infiltration of immune cells have all been related to post-burn local and systemic pathology. This "narrative" review explores the current state of knowledge, focusing on both the local and systemic immunology post-burn, and further questions how it is linked to the clinical outcome. Moreover, it illustrates the complexity of post-burn immunology and the existing gaps in knowledge on underlying mechanisms of burn pathology.
Burns are a significant cause of trauma, and over the years, the focus of patient care has shifted from just survival to facilitation of improved functional outcomes. Typically, burn treatment, ...especially in the case of extensive burn injuries, involves surgical excision of injured skin and reconstruction of the burn injury with the aid of skin substitutes. Conventional skin substitutes do not contain all skin cell types and do not facilitate recapitulation of native skin physiology. Three-dimensional (3D) bioprinting for reconstruction of burn injuries involves layer-by-layer deposition of cells along with scaffolding materials over the injured areas. Skin bioprinting can be done either in situ or in vitro. Both these approaches are similar except for the site of printing and tissue maturation. There are technological and regulatory challenges that need to be overcome for clinical translation of bioprinted skin for burn reconstruction. However, the use of bioprinting for skin reconstruction following burns is promising; bioprinting will enable accurate placement of cell types and precise and reproducible fabrication of constructs to replace the injured or damaged sites. Overall, 3D bioprinting is a very transformative technology, and its use for wound reconstruction will lead to a paradigm shift in patient outcomes. In this review, we aim to introduce bioprinting, the different stages involved, in vitro and in vivo skin bioprinting, and the various clinical and regulatory challenges in adoption of this technology.
Abstract Although hypertrophic scarring commonly occurs following burns, many aspects such as incidence of and optimal treatment for scar hypertrophy remain unclear. This review will focus on ...hypertrophic scar formation after burn in particular, exploring multiple treatment options and describing their properties as well as effectiveness. To evaluate treatment efficacy and scar development, clinical scar assessment is of eminent importance. Furthermore, recommendations regarding the classification of hypertrophy in the daily practice and in clinical trials are implemented.
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