Magda M.W. Ulrich

Prevention and curative management of hypertrophic scar formation

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.

Biological background of dermal substitutes

Dermal substitutes are of major importance in treating full thickness skin defects, both in acute and chronic wounds. In this review we will outline specific requirements of three classes of dermal substitutes: Biological and clinical requirements will be translated to composition, physical structure, immunological properties and cell-matrix interactions of the various materials. Important properties like pore size, cell adhesion sites (e.g. RGD sequences), crosslinking, degradability and the presence of a basement membrane will be discussed for each of the different classes of materials.

Currently known risk factors for hypertrophic skin scarring: A review

OBJECTIVE The study aims to provide an overview of risk factors for hypertrophic scarring. BACKGROUND Hypertrophic skin scarring remains a major concern in medicine and causes considerable morbidity. Despite extensive research on this topic, the precise mechanism of excessive scarring is still unknown. In addition, the current literature lacks an overview of the possible risk factors in the development of hypertrophic scars. METHODS PubMed searches were performed on risk factors for hypertrophic scar (HTS) formation. RESULTS Eleven studies suggesting nine factors associated with HTS formation were found. Studies concerning chemotherapy, age, stretch, infection, and smoking have a moderate to high strength of evidence, but some other factors have not been studied in a convincing manner or are still disputed. CONCLUSIONS Risk factors for HTS formation are young age, bacterial colonization, and skin subjected to stretch. Chemotherapy, statins, and smoking seem to play a protective role in HTS formation.

Altered TGF-β signaling in fetal fibroblasts: What is known about the underlying mechanisms?

Scarless wound healing is a unique and intrinsic capacity of the fetal skin that is not fully understood. Further insight into the underlying mechanisms of fetal wound healing may lead to new therapeutic approaches promoting adult scarless wound healing. Differences between fetal and adult wound healing are found in the extracellular matrix, the inflammatory reaction and the levels of growth factors present in the wound. This review focuses specifically on transforming growth factor β (TGF‐β), as this growth factor is prominently involved in wound healing and fibroblast‐to‐myofibroblast differentiation.

Extracellular matrix components of oral mucosa differ from skin and resemble that of foetal skin

OBJECTIVE Wounds of both the oral mucosa and early-to-mid gestation foetuses have a propensity to heal scarless. Repair of skin wounds in adults, however, regularly results in scar formation. The extracellular matrix (ECM) plays an important role in the process of healing. The fate of scarless or scar forming healing may already be defined by the ECM composition, prior to wounding. In this study, the presence of several ECM components in oral mucosa (palatum) and skin was investigated. DESIGN Immunohistochemical stainings of different ECM components were performed on skin, obtained from abdominal dermolipectomy surgery, and oral mucosa, derived after pharynx reconstruction. RESULTS Expression of fibronectin, its splice variant ED-A, and chondroitin sulphate was elevated in oral tissue, whereas elastin expression was higher in skin. Tenascin-C, hyaluronic acid, biglycan, decorin, and syndecan-1 were expressed at similar levels in both tissues. Oral mucosa contained more blood vessels than skin samples. Finally, oral keratinocytes proliferated more, while dermal keratinocytes demonstrated higher differentiation. CONCLUSIONS Comparing ECM components of the skin and oral mucosa coincides with differences earlier observed between foetal and adult skin, and this might indicate that some ECM components are involved in the mode of repair.

Transforming growth factor-β (TGF-β) signaling in healthy human fetal skin: A descriptive study

BACKGROUND TGF-β plays an important role in growth and development but is also involved in scarring and fibrosis. Differences for this growth factor are known between scarless fetal wound healing and adult wound healing. Nonetheless, most of the data in this area are from animal studies or in vitro studies and, thus, information about the human situation is incomplete and scarce. OBJECTIVE The aim of this study was to compare the canonical TGF-β signaling in unwounded human fetal and adult skin. METHODS Q-PCR, immunohistochemistry, Western Blot and Luminex assays were used to determine gene expression, protein levels and protein localization of components of this pathway in healthy skin. RESULTS All components of the canonical TGF-β pathway were present in unwounded fetal skin. Compared to adult skin, fetal skin had differential concentrations of the TGF-β isoforms, had high levels of phosphorylated receptor-Smads, especially in the epidermis, and had low expression of several fibrosis-associated target genes. Further, the results indicated that the processes of receptor endocytosis might also differ between fetal and adult skin. CONCLUSION This descriptive study showed that there are differences in gene expression, protein concentrations and protein localization for most components of the canonical TGF-β pathway between fetal and adult skin. The findings of this study can be a starting point for further research into the role of TGF-β signaling in scarless healing.

Dectin-1 activation induces proliferation and migration of human keratinocytes enhancing wound re-epithelialization

Beta-glucans in temporary wound dressings have immuno-stimulatory capacities and have been shown to enhance wound healing in burn patients. Curdlan is a 1,3-linked bacterial/fungal derived beta-glucan that induces inflammatory responses via the C-type lectin receptor dectin-1 on dendritic cells (DCs). Here we investigated the effect of beta-glucan curdlan and the role of dectin-1 expressed by keratinocytes (KCs) in wound healing. Curdlan enhanced migration, proliferation and wound closure of human KCs in a dectin-1 dependent manner, both in vitro and ex vivo. Our data suggest that curdlan induces human KC proliferation and migration and could therefore be used in creams to enhance wound healing.

Stem cells in burn eschar.

This study compares mesenchymal cells isolated from excised burn wound eschar with adipose-derived stem cells (ASCs) and dermal fibroblasts in their ability to conform to the requirements for multipotent mesenchymal stem cells (MSCs). A population of multipotent stem cells in burn eschar could be an interesting resource for tissue engineering approaches to heal burn wounds. Cells from burn eschar, dermis, and adipose tissue were assessed for relevant CD marker profiles using flow cytometry and for their trilineage differentiation ability in adipogenic, osteogenic, and chondrogenic conditions. Although the different cell types did not differ significantly in their CD marker expression, the eschar-derived cells and ASCs readily differentiated into adipocytes, osteoblasts, and chondrocytes, while dermal fibroblasts only exhibited some chondrogenic potential. We conclude that the eschar-derived mesenchymal cells represent a population of multipotent stem cells. The origin of the cells from burn eschar remains unclear, but it is likely they represent a population of adult stem cells mobilized from other parts of the body in response to the burn injury. Their resemblance to ASCs could also be cause for speculation that in deep burns the subcutaneous adipose tissue might be an important stem cell source for the healing wound.

Outcome of Burns Treated With Autologous Cultured Proliferating Epidermal Cells: A Prospective Randomized Multicenter Intrapatient Comparative Trial.

Standard treatment for large burns is transplantation with meshed split skin autografts (SSGs). A disadvantage of this treatment is that healing is accompanied by scar formation. Application of autologous epidermal cells (keratinocytes and melanocytes) may be a suitable therapeutic alternative, since this may enhance wound closure and improve scar quality. A prospective, multicenter randomized clinical trial was performed in 40 adult patients with acute full thickness burns. On two comparable wound areas, conventional treatment with SSGs was compared to an experimental treatment consisting of SSGs in combination with cultured autologous epidermal cells (ECs) seeded in a collagen carrier. The primary outcome measure was wound closure after 5–7 days. Secondary outcomes were safety aspects and scar quality measured by graft take, scar score (POSAS), skin colorimeter (DermaSpectrometer®) and elasticity (Cutometer®). Wound epithelialization after 5–7 days was significantly better for the experimental treatment (71%) compared to the standard treatment (67%) (p = 0.034, Wilcoxon), whereas the take rates of the grafts were similar. No related adverse events were recorded. Scar quality was evaluated at 3 (n = 33) and 12 (n = 28) months. The POSAS of the observer after 3 and 12 months and of the patient after 12 months were significantly better for the experimental area. Improvements between 12% and 23% (p ≤ 0.010, Wilcoxon) were detected for redness, pigmentation, thickness, relief, and pliability. Melanin index at 3 and 12 months and erythema index at 12 months were closer to normal skin for the experimental treatment than for conventional treatment (p ≤ 0.025 paired samples t-test). Skin elasticity showed significantly higher elasticity (p = 0.030) in the experimental area at 3 months follow-up. We showed a safe application and significant improvements of wound healing and scar quality in burn patients after treatment with ECs versus SSGs only. The relevance of cultured autologous cells in treatment of extensive burns is supported by our current findings.

Burn injury suppresses human dermal dendritic cell and Langerhans cell function.

Human skin contains epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) that are key players in induction of adaptive immunity upon infection. After major burn injury, suppressed adaptive immunity has been observed in patients. Here we demonstrate that burn injury affects adaptive immunity by altering both epidermal LC and dermal DC functions. We developed a human ex vivo burn injury model to study the function of DCs in thermally injured skin. No differences were observed in the capacity of both LCs and dermal DCs to migrate out of burned skin compared to unburned skin. Similarly, expression levels of co-stimulatory molecules were unaltered. Notably, we observed a strong reduction of T cell activation induced by antigen presenting cell (APC) subsets that migrated from burned skin through soluble burn factors. Further analyses demonstrated that both epidermal LCs and dermal DCs have a decreased T cell stimulatory capacity after burn injury. Restoring the T cell stimulatory capacity of DC subsets might improve tissue regeneration in patients with burn wounds.