Current Approaches to Wound Repair in Burns: How far Have we Come From Cover to Close? A Narrative Review.

Burn injuries are a significant global health concern, with more than 11 million people requiring medical intervention each year and approximately 180,000 deaths annually. Despite progress in health and social care, burn injuries continue to result in socioeconomic burdens for victims and their families. The management of severe burn injuries involves preventing and treating burn shock and promoting skin repair through a two-step procedure of covering and closing the wound. Currently, split-thickness/full-thickness skin autografts are the gold standard for permanent skin substitution. However, deep burns treated with split-thickness skin autografts may contract, leading to functional and appearance issues. Conversely, defects treated with full-thickness skin autografts often result in more satisfactory function and appearance. The development of tissue-engineered dermal templates has further expanded the scope of wound repair, providing scar reductive and regenerative properties that have extended their use to reconstructive surgical interventions. Although their interactions with the wound microenvironment are not fully understood, these templates have shown potential in local infection control. This narrative review discusses the current state of wound repair in burn injuries, focusing on the progress made from wound cover to wound closure and local infection control. Advancements in technology and therapies hold promise for improving the outcomes for burn injury patients. Understanding the underlying mechanisms of wound repair and tissue regeneration may provide new insights for developing more effective treatments in the future.

Heterogeneous response to TGF-ß1/3 isoforms in fibroblasts of different origins: implications for wound healing and tumorigenesis.

Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-ß1 and TGF-ß3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-ß1 vs. TGF-ß3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-ß1 and TGF-ß3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-ß1/3 treatments. In general, TGF-ß1 demonstrated a more potent activation of signaling pathways compared to TGF-ß3, whereas TGF-ß3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-ß signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-ß isomers considering inherent fibroblast heterogeneity.

Agrimonia eupatoria L. Aqueous Extract Improves Skin Wound Healing: An In Vitro Study in Fibroblasts and Keratinocytes and In Vivo Study in Rats.

BACKGROUND/AIM: We have previously shown that the water extract of Agrimonia eupatoria L. (AE) is a valuable source of polyphenols with excellent antioxidant properties and has clinical potential for the prevention and/or adjuvant therapy of cardiovascular complications associated with diabetes. Inspired by our previously published data, in the present study we examined whether AE improves skin wound healing in a series of in vitro and in vivo experiments. MATERIALS AND METHODS: In detail, we investigated the ability of the AE extract to induce fibroblast to myofibroblast conversion, extracellular matrix (ECM) deposition, and keratinocyte proliferation/differentiation, in vitro. In parallel, in an animal model, we measured wound tensile strength (TS) and assessed the progression of open wounds using basic histology and immunofluorescence. RESULTS: The AE extract induced the myofibroblast-like phenotype and enhanced ECM deposition, both in vitro and in vivo. Furthermore, the wound TS of skin incisions and the contraction rates of open excisions were significantly increased in the AE-treated group. CONCLUSION: The present data show that AE water extract significantly improves the healing of open and sutured skin wounds. Therefore, our data warrant further testing in animal models that are physiologically and evolutionarily closer to humans.

Psychological Aspects in Early Adjustment After Severe Burn Injury.

Burn injury is one of the most serious traumatic events with possible psychological and psychosocial consequences. Health status perception is one of the main health outcomes. The severity of psychological symptoms does not always correlate with that of the burn injury, suggesting that early screening for psychological vulnerabilities may be beneficial. The aim of our study was to identify the personality, clinical, and sociodemographic characteristics related to patient's subjective perception of health, depression, and anxiety in a sample of 52 adult patients with severe burn injury shortly before discharge from specialty burn clinic. Subjective health perception was predicted by depression (ß = -.143, t(47) = -3.94, P < .001) and neuroticism (ß = -.106, t(43) = -4.83, P < .001), and it correlated positively with extraversion (r = .2858, P = .0465) and conscientiousness (r = .3663, P = .0096). Depression was predicted by neuroticism (F(1,49) = 18.4; P < .001) and correlated with attachment avoidance (r = .29, P = .0383) and negatively with extraversion (r = -.32, P = .0220). Anxiety was related to attachment anxiety (F(1,49) = 4.25; P = .045), neuroticism (F(1,49) = 15.75; P < .001), and agreeableness (r = -.36, P = .0101). Unemployed patients experienced higher levels of depression and anxiety. This research suggests that personality traits and adult attachment may play an important role in the acute phase of the recovery from a severe burn injury. These findings can be relevant for early intervention and holistic rehabilitation.

Novel lipophosphonoxin-loaded polycaprolactone electrospun nanofiber dressing reduces Staphylococcus aureus induced wound infection in mice.

Active wound dressings are attracting extensive attention in soft tissue repair and regeneration, including bacteria-infected skin wound healing. As the wide use of antibiotics leads to drug resistance we present here a new concept of wound dressings based on the polycaprolactone nanofiber scaffold (NANO) releasing second generation lipophosphonoxin (LPPO) as antibacterial agent. Firstly, we demonstrated in vitro that LPPO released from NANO exerted antibacterial activity while not impairing proliferation/differentiation of fibroblasts and keratinocytes. Secondly, using a mouse model we showed that NANO loaded with LPPO significantly reduced the Staphylococcus aureus counts in infected wounds as evaluated 7 days post-surgery. Furthermore, the rate of degradation and subsequent LPPO release in infected wounds was also facilitated by lytic enzymes secreted by inoculated bacteria. Finally, LPPO displayed negligible to no systemic absorption. In conclusion, the composite antibacterial NANO-LPPO-based dressing reduces the bacterial load and promotes skin repair, with the potential to treat wounds in clinical settings.

Burn-Induced Cardiac Dysfunction: A Brief Review and Long-Term Consequences for Cardiologists in Clinical Practice.

BACKGROUND: Severe burn injury is a specific type of trauma, which induces a unique complex of responses in the body and leads to an extreme increase in stress hormones and proinflammatory cytokines. These hypermetabolic and stress responses are desirable in the acute phase but can persist for several years and lead - due to several mechanisms - to many late complications, including myocardial dysfunction. METHODS: The databases of PubMed, ScienceDirect, National Institutes of Health (NIH) of the United States, and Google Scholar were searched. Studies relevant to the topic of late cardiovascular dysfunction after burn injury were compiled using key words. RESULTS: Burn-induced heart disease significantly increases morbidity and mortality and contributes to the reduction in the quality of life of patients after severe burn trauma. A variety of mechanisms causing myocardial dysfunction after burn trauma have been detailed but understanding all of the exact consequences is limited, especially regarding chronic cardiovascular changes. CONCLUSION: A detailed understanding of the pathophysiology of chronic cardiac changes can contribute to a comprehensive and preventive treatment plan and improve long-term outcomes of burn patients.

Molecular Changes Underlying Hypertrophic Scarring Following Burns Involve Specific Deregulations at All Wound Healing Stages (Inflammation, Proliferation and Maturation).

Excessive connective tissue accumulation, a hallmark of hypertrophic scaring, results in progressive deterioration of the structure and function of organs. It can also be seen during tumor growth and other fibroproliferative disorders. These processes result from a wide spectrum of cross-talks between mesenchymal, epithelial and inflammatory/immune cells that have not yet been fully understood. In the present review, we aimed to describe the molecular features of fibroblasts and their interactions with immune and epithelial cells and extracellular matrix. We also compared different types of fibroblasts and their roles in skin repair and regeneration following burn injury. In summary, here we briefly review molecular changes underlying hypertrophic scarring following burns throughout all basic wound healing stages, i.e. during inflammation, proliferation and maturation.

Impact of Antibiotics Associated with the Development of Toxic Epidermal Necrolysis on Early and Late-Onset Infectious Complications.

Toxic epidermal necrolysis (TEN) is a rare disease, which predominantly manifests as damage to the skin and mucosa. Antibiotics count among the most common triggers of this hypersensitive reaction. Patients with TEN are highly susceptible to infectious complications due to the loss of protective barriers and immunosuppressant therapy. The aim of this study was to investigate the potential relationship between antibiotics used before the development of TEN and early and late-onset infectious complications in TEN patients. In this European multicentric retrospective study (Central European Lyell syndrome: therapeutic evaluation (CELESTE)), records showed that 18 patients with TEN used antibiotics (mostly aminopenicillins) before the disease development (group 1), while in 21 patients, TEN was triggered by another factor (group 2). The incidence of late-onset infectious complications (5 or more days after the transfer to the hospital) caused by Gram-positive bacteria (especially by Enterococcus faecalis/faecium) was significantly higher in group 1 than in group 2 (82.4% vs. 35.0%, p = 0.007/p corr = 0.014) while no statistically significant difference was observed between groups of patients with infection caused by Gram-negative bacteria, yeasts, and filamentous fungi (p > 0.05). Patients with post-antibiotic development of TEN are critically predisposed to late-onset infectious complications caused by Gram-positive bacteria, which may result from the dissemination of these bacteria from the primary focus.

Complex approach to skin repair in an extensively burned child: a case study.

The limited amount of donor sites and loss of dermis are major challenges in the therapy of extensively burned patients. Here, we present a complex treatment approach of an eight-year-old boy with full-thickness burns on 90% of the total body surface area, using simple and efficient techniques of tissue engineering. To obtain sufficient skin for grafting we repeatedly harvested the same anatomical areas. Acceleration of donor site healing was achieved by treatment with a suspension of noncultured autologous skin cells (NASC) and acellular porcine dermis (Xe-Derma (XD), Czech Republic). Moreover, such wound management allowed up to six reharvestings, compared with one-to-three procedures following routine treatment. Bilayer Integra template (Integra LifeSciences Corp., US) was used as the dermal substitute in over 60% of full-thickness burns. Following successful vascularisation of the neodermis in 3-4 weeks, the templates were covered with meshed split-thickness skin grafts (STSG), or Meek autografts, and facilitated by NASC/XD. We may conclude that such a 'sandwich' technique approach, combining four biological covers (Integra, STSG, NASC and XD), significantly contributed to the successful skin repair of the patient.

Aesculus hippocastanum L. Extract Does Not Induce Fibroblast to Myofibroblast Conversion but Increases Extracellular Matrix Production In Vitro Leading to Increased Wound Tensile Strength in Rats.

The ability of horse chestnut extract (HCE) to induce contraction force in fibroblasts, a process with remarkable significance in skin repair, motivated us to evaluate its wound healing potential in a series of experiments. In the in vitro study of the ability of human dermal fibroblasts to form myofibroblast-like cells was evaluated at the protein level (Western blot and immunofluorescence). The in vivo study was conducted on male Sprague-Dawley rats with inflicted wounds (one open circular and one sutured incision) on their backs. Rats were topically treated with two tested HCE concentrations (0.1% and 1%) or sterile water. The control group remained untreated. The incisions were processed for wound tensile strength (TS) measurement whereas the open wounds were subjected to histological examination. On the in vitro level the HCE extract induced fibronectin-rich extracellular matrix formation, but did not induced α-smooth muscle actin (SMA) expression in dermal fibroblasts. The animal study revealed that HCE increased wound TS and improved collagen organization. In conclusion, the direct comparison of both basic wound models demonstrated that the healing was significantly increased following HCE, thus this extract may be found useful to improve healing of acute wounds. Nevertheless, the use of an experimental rat model warrants a direct extrapolation to the human clinical situation.

Poly-ε-caprolactone and polyvinyl alcohol electrospun wound dressings: adhesion properties and wound management of skin defects in rabbits.

Aim: This study evaluates the effect of electrospun dressings in critical sized full-thickness skin defects in rabbits. Materials & methods: Electrospun poly-ε-caprolactone (PCL) and polyvinyl alcohol (PVA) nanofibers were tested in vitro and in vivo. Results: The PCL scaffold supported the proliferation of mesenchymal stem cells, fibroblasts and keratinocytes. The PVA scaffold showed significant swelling, high elongation capacity, limited protein adsorption and stimulation of cells. Nanofibrous dressings improved wound healing compared with the control group in vivo. A change of the PCL dressing every 7 days resulted in a decreased epithelial thickness and type I collagen level in the adhesive group, indicating peeling off of the newly formed tissue. In the PVA dressings, the exchange did not affect healing. Conclusion: The results demonstrate the importance of proper dressing exchange.

A histological analysis of artificial skin in an extensively burned child, 14 years after application: a case report.

INTRODUCTION: Artificial skin has become the treatment of choice in extensive, full-thickness thermal injuries. The longest follow-up of the healing process in burn sites covered with the Integra Bilayer Matrix Wound Dressing onto the wound published to date was at around five years after application. In our case report, we describe the clinical and histological analysis of an extensive, full-thickness thermal injury 14 years on from treatment with the bilayer matrix wound dressing. CASE STUDY: A nine-year-old boy suffered a full-thickness skin loss over 85% of his body surface area following a fire accident. The bilayer matrix wound dressing was used on both legs and covered almost 30% of his body surface area. Cosmetic and functional results were satisfactory. Histological analysis performed nine years after the application of the bilayer matrix wound dressing onto the wound showed a double-layered skin composition with changes in the fibrous component of the dermis. CONCLUSION: Despite satisfactory short- and long-term clinical results from applications of the bilayer matrix wound dressing, we found important differences in microstructure when compared with the physiological condition.

Human keratinocyte growth and differentiation on acellular porcine dermal matrix in relation to wound healing potential.

A number of implantable biomaterials derived from animal tissues are now used in modern surgery. Xe-Derma is a dry, sterile, acellular porcine dermis. It has a remarkable healing effect on burns and other wounds. Our hypothesis was that the natural biological structure of Xe-Derma plays an important role in keratinocyte proliferation and formation of epidermal architecture in vitro as well as in vivo. The bioactivity of Xe-Derma was studied by a cell culture assay. We analyzed growth and differentiation of human keratinocytes cultured in vitro on Xe-Derma, and we compared the results with formation of neoepidermis in the deep dermal wounds treated with Xe-Derma. Keratinocytes cultured on Xe-Derma submerged in the culture medium achieved confluence in 7-10 days. After lifting the cultures to the air-liquid interface, the keratinocytes were stratified and differentiated within one week, forming an epidermis with basal, spinous, granular, and stratum corneum layers. Immunohistochemical detection of high-molecular weight cytokeratins (HMW CKs), CD29, p63, and involucrin confirmed the similarity of organization and differentiation of the cultured epidermal cells to the normal epidermis. The results suggest that the firm natural structure of Xe-Derma stimulates proliferation and differentiation of human primary keratinocytes and by this way improves wound healing.

Nanofibers prepared by needleless electrospinning technology as scaffolds for wound healing.

Electrospun gelatin and poly-ε-caprolactone (PCL) nanofibers were prepared using needleless technology and their biocompatibility and therapeutic efficacy have been characterized in vitro in cell cultures and in an experimental model of a skin wound. Human dermal fibroblasts, keratinocytes and mesenchymal stem cells seeded on the nanofibers revealed that both nanofibers promoted cell adhesion and proliferation. The effect of nanofibers on wound healing was examined using a full thickness wound model in rats and compared with a standard control treatment with gauze. Significantly faster wound closure was found with gelatin after 5 and 10 days of treatment, but no enhancement with PCL nanofibers was observed. Histological analysis revealed enhanced epithelialisation, increased depth of granulation tissue and increased density of myofibroblasts in the wound area with gelatin nanofibers. The results show that gelatin nanofibers produced by needleless technology accelerate wound healing and may be suitable as a scaffold for cell transfer and skin regeneration.

New biological temporary skin cover Xe-Derma(®) in the treatment of superficial scald burns in children.

BACKGROUND: Xe-Derma® is a new dry sterile biological cover derived from acellular pig dermis. Hydrated Xe-Derma® displays bio-mechanical features similar to the normal skin. The aim of the present study was to compare the efficacy of Xe-Derma® with hydrocolloid dressing Askina THINSite® for treatment of superficial burns in children in a prospective study. MATERIALS AND METHODS: In a prospective study, 86 patients (5 months to 7 years of age) with superficial scald burns on a surface area of 1-35% BSA were enrolled. In the course of the study, 43 patients were treated with Xe-Derma® and 43 patients with Askina THINSite®. We collected data including the percentage of BSA covered with biological or synthetic material, epithelization time, the number of complete conversions (deepening of 100% of covered area into deep dermal wound) under each cover, the number and extent of partial conversions (deepening of less then 100% of covered area into deep dermal wound), infectious complications, the number of reapplications of the temporary cover and the extent in square centimetres of dressing material needed for successful healing of 1% BSA. RESULTS: No significant difference in the epithelization time, percentage of conversion from superficial to deep dermal burns and percentage of infectious complication was detected between the two groups. However, patients in the Xe-Derma® group were burned on a more extensive burn surface area (p ≤ 0.028). Xe-Derma® showed adherence to the wound and therefore there has been no need to be changed The number of reapplications and therefore also the number of square centimetres needed for successful healing of 1% BSA were statistically higher in the Askina THINSite® group (p < 0.01) due to increased secretion and accumulation of fluid underneath this hydrocoloid cover. The minimal frequency of changes of this biological cover material brings a significant benefit to pediatric patients. CONCLUSION: Acellular pig dermis Xe-Derma® represents a reliable biological cover material. It is an advantageous alternative to synthetic temporary skin covers in the treatment of superficial scald burns in children.