Identification of IGF2 promotes skin wound healing by co-expression analysis.

Oral mucosa is an ideal model for studying scarless wound healing. Researchers have shown that the key factors which promote scarless wound healing already exist in basal state of oral mucosa. Thus, to identify the other potential factors in basal state of oral mucosa will benefit to skin wound healing. In this study, we identified eight gene modules enriched in wound healing stages of human skin and oral mucosa through co-expression analysis, among which the module M8 was only module enriched in basal state of oral mucosa, indicating that the genes in module M8 may have key factors mediating scarless wound healing. Through bioinformatic analysis of genes in module M8, we found IGF2 may be the key factor mediating scarless wound healing of oral mucosa. Then, we purified IGF2 protein by prokaryotic expression, and we found that IGF2 could promote the proliferation and migration of HaCaT cells. Moreover, IGF2 promoted wound re-epithelialization and accelerated wound healing in a full-thickness skin wound model. Our findings identified IGF2 as a factor to promote skin wound healing which provide a potential target for wound healing therapy in clinic.

Emulgel based on fish skin collagen-microalgae-silver increased neovascularization and re-epithelialization of full thickness burn in rats.

Deep skin burn represents a global morbidity and mortality problem, and the limitation of topical treatment agents has motivated research to development new formulations capable of preventing infections and accelerating healing. The aim of this work was to develop and characterize an emulgel based on collagen (COL) and gelatin (GEL) extracted from fish skin associated with Chlorella vulgaris extract (CE) and silver nitrate (AgNO3). COL and GEL were characterized by physicochemical and thermal analyses; and CE by electrophoresis and its antioxidant capacity. Three emulgels formulations were developed: COL (0.5%) + GEL (2.5%) (E1), COL+GEL+CE (1%) (E2), and COL+GEL+CE + AgNO3 (0.1%) (E3). All formulations were characterized by physicochemical, rheology assays, and preclinical analyses: cytotoxicity (in vitro) and healing potential using a burn model in rats. COL and GEL showed typical physicochemical characteristics, and CE presented 1.3 mg/mL of proteins and antioxidant activity of 76%. Emulgels presented a coherent physicochemical profile and pseudoplastic behavior. Preclinical analysis showed concentration-dependent cytotoxicity against fibroblast and keratinocytes. In addition, all emulgels induced similar percentages of wound contraction and complete wound closure in 28 days. The histopathological analysis showed higher scores for polymorphonuclear cells to E1 and greater neovascularization and re-epithelialization to E3. Then, E3 formulation has potential to improve burn healing, although its use in a clinical setting requires further studies.

Combined Amniotic Membrane and Self-Powered Electrical Stimulator Bioelectronic Dress Promotes Wound Healing.

Human amniotic membranes (hAMs) are widely used as wound management biomaterials, especially as grafts for corneal reconstruction due to the structure of the extracellular matrix and excellent biological properties. However, their fragile nature and rapid degradation rate hinder widespread clinical use. In this work, we engineered a novel self-powered electronic dress (E-dress), combining the beneficial properties of an amniotic membrane and a flexible electrical electrode to enhance wound healing. The E-dress displayed a sustained discharge capacity, leading to increased epidermal growth factor (EGF) release from amniotic mesenchymal interstitial stem cells. Live/dead staining, CCK-8, and scratch-wound-closure assays were performed in vitro. Compared with amniotic membrane treatment alone, the E-dress promoted cell proliferation and migration of mouse fibroblast cells and lower cytotoxicity. In a mouse full-skin defect model, the E-dress achieved significantly accelerated wound closure. Histological analysis revealed that E-dress treatment promoted epithelialization and neovascularization in mouse skin. The E-dress exhibited a desirable flexibility that aligned with tissue organization and displayed maximum bioactivity within a short period to overcome rapid degradation, implying great potential for clinical applications.

Multi-functional bandage - bioactive glass/metal oxides/alginate composites based regenerative membrane facilitating re-epithelialization in diabetic wounds with sustained drug delivery and anti-bactericidal efficacy.

Chronic wounds, especially diabetic, foot and pressure ulcers are a major health problem affecting >10 % of the world's populace. Calcium phosphate materials, particularly, bioactive glasses (BG), used as a potential material for hard and soft tissue repair. This study combines nanostructured 45S5 BG with titania (TiO2) and alumina (Al2O3) into a composite via simple sol-gel method. Prepared composites with alginate (Alg) formed a bioactive nanocomposite hydrogel membrane via freezing method. X-ray diffraction revealed formation of two phases such as Na1.8Ca1.1Si6O14 and ß-Na2Ca4(PO4)2SiO4 in the silica network. Fourier transformed InfraRed spectroscopy confirmed the network formation and cross-linking between composite and alginate. <2 % hemolysis, optimal in vitro degradation and porosity was systematically evaluated up to 7 days, resulting in increasing membrane bioactivity. Significant cytocompatibility, cell migration and proliferation and a 3-4-fold increase in Collagen (Col) and Vascular Endothelial Growth Factor (VEGF) expression were obtained. Sustained delivery of 80 % Dox in 24 h and effective growth reduction of S. aureus and destruction of biofilm development against E. coli and S. aureus within 24 h. Anatomical fin regeneration, rapid re-epithelialization and wound closure were achieved within 14 days in both zebrafish and in streptozotocin (STZ) induced rat in vivo animal models with optimal blood glucose levels. Hence, the fabricated bioactive membrane can act as effective wound dressing material, for diabetic chronic infectious wounds.

Thermoresponsive keratin-methylcellulose self-healing injectable hydrogel accelerating full-thickness wound healing by promoting rapid epithelialization.

Chronic wounds suffer from impaired healing due to microbial attack and poor vascular growth. Thermoresponsive hydrogels gained attention in wound dressing owing to their gelation at physiological temperature enabling them to take the shape of asymmetric wounds. The present study delineates the development of thermoresponsive hydrogel (MCK), from hair-derived keratin (K) and methylcellulose (MC) in the presence of sodium sulfate. The gelation temperature (Tg) of this hydrogel is in the range of 30 °C to 33 °C. Protein-polymer interaction leading to thermoreversible sol-gel transition involved in MCK blends has been analyzed and confirmed by FTIR, XRD, and thermal studies. Keratin, has introduced antioxidant properties to the hydrogel imparted cytocompatibility towards human dermal fibroblasts (HDFs) as evidenced by both MTT and live dead assays. In vitro wound healing assessment has been shown by enhanced migration of HDFs in the presence of MCK hydrogel compared to the control. Also, CAM assay and CD31 expression by the Wistar rat model has shown increased blood vessel branching after the implantation of MCK hydrogel. Further, in vivo study, demonstrated MCK efficacy of hydrogel in accelerating full-thickness wounds with minimal scarring in Wistar rats, re-epithelialization, and reinstatement of the epidermal-dermal junction thereby exhibiting clinical relevance for chronic wounds.

Unique combination of hyaluronic acid and amino acids in the management of patients with a range of moderate-to-severe chronic wounds: Evidence from international clinical trials.

Chronic wounds present a prolonged burden to patients, their families and healthcare systems. There is evidence that the unique combination of hyaluronic acid (HA) and amino acids (Vulnamin®) promotes re-epithelialization of wounds and stimulates activation and proliferation of fibroblasts with a significant increase in the regeneration of epithelial cells. Tissue regeneration and tissue repair are considered to be the fundamental activities of this unique combination of HA and amino acids that distinguishes it from other wound healing products. A review of trials over the last 15 years indicates distinct advantages of the unique combination of HA and amino acids, in terms of healing rate and induction of granulation tissue production compared with HA alone.

Arginine-Nanoenzyme with Timely Angiogenesis for Promoting Diabetic Wound Healing.

The successful treatment of diabetic wounds requires strategies that promote anti-inflammation, angiogenesis, and re-epithelialization of the wound. Excessive oxidative stress in diabetic ulcers (DUs) inhibits cell proliferation and hinders timely vascular formation and macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2, resulting in a persistent inflammatory environment and a nonhealing wound. We designed arginine-nanoenzyme (FTA) with mimic-catalase and arginine-loading. 2,3,4-trihydroxy benzaldehyde and arginine (Arg) were connected by a Schiff base bond, and the nanoassembly of Arg to FTA was driven by the coordination force between a ferric ion and polyphenol and noncovalent bond force such as a hydrogen bond. FTA could remove excess reactive oxygen species at the wound site in situ and convert it to oxygen to improve hypoxia. Meanwhile, Arg was released and catalytically metabolized by NO synthase in M1 to promote vascular repair in the early phase. In the late phase, the metabolite of Arg catalyzed by arginase in M2 was mainly ornithine, which played a vital role in promoting tissue repair, which implemented angiogenesis timely and prevented hypertrophic scars. Mechanistically, FTA activated the cAMP signaling pathway combined with reducing inflammation and ameliorating angiogenesis, which resulted in excellent therapeutic effects on a DU mice model.

In Vivo Wound Healing Model for Characterization of Gene Electrotransfer Effects in Mouse Skin.

Wound healing is a complex biological response to injury characterized by a sequence of interdependent and overlapping physiological actions. To study wound healing and cutaneous regeneration processes, the complexity of wound healing requires the use of animal models. In this chapter, we describe the protocol to generate skin wounds in a mouse model. In the mouse splinted excisional wound model, two full-thickness wounds are firstly created on the mouse dorsum, which is followed by application of silicone splint around wounded area. A splinting ring tightly adheres to the skin around full-thickness wound, preventing wound contraction and replicating human processes of re-epithelialization and new tissue formation. The wound is easily accessible for treatment as well as for daily monitoring and quantifying the wound closure.This technique represents valuable approach for the study of wound healing mechanisms and for evaluation of new therapeutic modalities. In this protocol, we describe how to utilize the model to study the effect of gene electrotransfer of plasmid DNA coding for antiangiogenic molecules. Additionally, we also present how to precisely regulate electrical parameters and modify electrode composition to reach optimal therapeutic effectiveness of gene electrotransfer into skin around wounded area.

Emerging trends in the application of hydrogel-based biomaterials for enhanced wound healing: A literature review.

Currently, there is a rising global incidence of diverse acute and chronic wounds, underscoring the immediate necessity for research and treatment advancements in wound repair. Hydrogels have emerged as promising materials for wound healing due to their unique physical and chemical properties. This review explores the classification and characteristics of hydrogel dressings, innovative preparation strategies, and advancements in delivering and releasing bioactive substances. Furthermore, it delves into the functional applications of hydrogels in wound healing, encompassing areas such as infection prevention, rapid hemostasis and adhesion adaptation, inflammation control and immune regulation, granulation tissue formation, re-epithelialization, and scar prevention and treatment. The mechanisms of action of various functional hydrogels are also discussed. Finally, this article also addresses the current limitations of hydrogels and provides insights into their potential future applications and upcoming innovative designs.

Reepithelialization of Diabetic Skin and Mucosal Wounds Is Rescued by Treatment With Epigenetic Inhibitors.

Wound healing is a complex, highly regulated process and is substantially disrupted by diabetes. We show here that human wound healing induces specific epigenetic changes that are exacerbated by diabetes in an animal model. We identified epigenetic changes and gene expression alterations that significantly reduce reepithelialization of skin and mucosal wounds in an in vivo model of diabetes, which were dramatically rescued in vivo by blocking these changes. We demonstrate that high glucose altered FOXO1-matrix metallopeptidase 9 (MMP9) promoter interactions through increased demethylation and reduced methylation of DNA at FOXO1 binding sites and also by promoting permissive histone-3 methylation. Mechanistically, high glucose promotes interaction between FOXO1 and RNA polymerase-II (Pol-II) to produce high expression of MMP9 that limits keratinocyte migration. The negative impact of diabetes on reepithelialization in vivo was blocked by specific DNA demethylase inhibitors in vivo and by blocking permissive histone-3 methylation, which rescues FOXO1-impaired keratinocyte migration. These studies point to novel treatment strategies for delayed wound healing in individuals with diabetes. They also indicate that FOXO1 activity can be altered by diabetes through epigenetic changes that may explain other diabetic complications linked to changes in diabetes-altered FOXO1-DNA interactions. ARTICLE HIGHLIGHTS: FOXO1 expression in keratinocytes is needed for normal wound healing. In contrast, FOXO1 expression interferes with the closure of diabetic wounds. Using matrix metallopeptidase 9 as a model system, we found that high glucose significantly increased FOXO1-matrix metallopeptidase 9 interactions via increased DNA demethylation, reduced DNA methylation, and increased permissive histone-3 methylation in vitro. Inhibitors of DNA demethylation and permissive histone-3 methylation improved the migration of keratinocytes exposed to high glucose in vitro and the closure of diabetic skin and mucosal wounds in vivo. Inhibition of epigenetic enzymes that alter FOXO1-induced gene expression dramatically improves diabetic healing and may apply to other conditions where FOXO1 has a detrimental role in diabetic complications.

Inhibition of the CoREST Repressor Complex Promotes Wound Re-Epithelialization through the Regulation of Keratinocyte Migration.

Wound healing is a complex process involving phases of hemostasis, inflammation, proliferation, and remodeling. The regenerative process in the skin requires coordination between many regulators, including signaling molecules, transcription factors, and the epigenetic machinery. In this study, we show that chromatin regulators HDAC1 and LSD1, key components of the CoREST repressor complex, are upregulated in the regenerating epidermis during wound repair. We also show that corin, a synthetic dual inhibitor of the CoREST complex and HDAC1/LSD1 activities, significantly accelerates wound closure through enhanced re-epithelialization in a mouse tail wound model. Acetylated H3K9 (methylation of histone H3 at lysine 9) expression, a histone modification targeted by HDAC1, is increased in keratinocytes after topical treatment with 100 nM and 1 µM of corin. In vitro experiments demonstrate that corin promotes migration and inhibits the proliferation of human keratinocytes. Furthermore, expression levels of genes promoting keratinocyte migration, such as AREG, CD24, EPHB2, ITGAX, PTGS, SCT1, SERPINB2, SERPINE1, SLPI, SNAI2, and TWIST, increased in keratinocytes treated with corin. These data demonstrate that dual inhibition of class I histone deacetylases and LSD1 by corin may serve as a new approach for promoting wound re-epithelialization and provide a platform for further applications of corin for the treatment of chronic wounds.

Aging Skin and Wound Healing.

Responsible for many essential functions of life, human skin is made up of many components, each of which undergoes significant functional changes with aging and photodamage. Wound healing was previously thought to be defective in the elderly given the higher presence of chronic wounds and the longer time required for re-epithelialization of acute wounds. However, these notions have been challenged in recent research, which has shown that wound healing in the elderly is delayed but not defective. Poor healing of chronic wounds in older populations is more often attributable to comorbid conditions rather than age alone.

Termografía infrarroja como método de diagnóstico en quemaduras: una revisión exploratoria de la literatura / Infrared thermography as a method of diagnosis in burns: an exploratory review of the literature

Objetivos: Revisar el uso y eficacia de la termografía infrarroja como instrumento diagnóstico y de medida de las quemaduras. Metodología: Se realizan 2 búsquedas, una general y otra específica, utilizando estrategia de búsqueda mediante un lenguaje controlado con términos MESH. Para seleccionar los artículos se filtra por título, resumen y palabras clave, además de aplicarse los criterios de inclusión y exclusión. Resultados: Durante la búsqueda general, se encontraron 165 artículos en PubMed, de los cuales 7 han sido seleccionados y 6 han sido incluidos. Mientras que con la búsqueda específica se obtienen 28 artículos, de los cuales se seleccionan 7 que no aparecían en la búsqueda general y se incluyen finalmente 6 de ellos. Conclusiones: La termografía infrarroja es un instrumento con mucho potencial y que ha mostrado buenos resultados, pero en ocasiones mucha variabilidad e inconsistencia, por lo que es necesaria la estandarización de una serie de medidas que nos permitan contrarrestar las dificultades a las que se expone y minimizar los sesgos, hecho que podrá mejorar más los resultados. Además, es necesaria una mayor investigación aplicando las variables térmicas encontradas para identificar el grado de influencia e importancia que tienen y comparar las diferentes modalidades de termografía infrarroja, estática y dinámica.(AU)

Objectives: To review the use and efficacy of infrared thermography as a diagnostic instrument and measurement of burns. Methodology: Two searches were carried out, one general and the other specific, using a controlled language search strategy with MESH terms. To select the articles we filtered them by title, abstract and key words, besides applying the inclusion and exclusion criteria. Results: During the general search, 165 articles were found in PubMed, of which 7 were selected and 6 were included. The specific search yielded 28 articles, of which 7 were selected that did not appear in the general search and 6 were finally included. Conclusions: Infrared thermography is an instrument with great potential that has shown good results but much variability and inconsistency at times, so it is necessary to standardize a series of measures that allow us to counteract the difficulties to which it is exposed and minimize biases, a fact that could further improve the results. In addition, further research is needed by applying the thermal variables found to identify the degree of influence and importance that they have and by comparing the different infrared thermography modalities, static and dynamic.(AU)

Epigallocatechin-3-gallate promotes wound healing response in diabetic mice by activating keratinocytes and promoting re-epithelialization.

Type 2 diabetes (T2D) is a metabolic disorder that causes numerous complications including impaired wound healing and poses a significant challenge for the management of diabetic patients. Epigallocatechin-3-gallate (EGCG) is a natural polyphenol that exhibits anti-inflammatory and anti-oxidative benefits in skin wounds, however, the direct effect of EGCG on epidermal keratinocytes, the primary cells required for re-epithelialization in wound healing remains unknown. Our study aims to examine the underlying mechanisms of EGCG's ability to promote re-epithelialization and wound healing in T2D-induced wounds. Murine models of wound healing in T2D were established via feeding high-fat high-fructose diet (HFFD) and the creation of full-thickness wounds. Mice were administered daily with EGCG or vehicle to examine the wound healing response and underlying molecular mechanisms of EGCG's protective effects. Systemic administration of EGCG in T2D mice robustly accelerated the wound healing response following injury. EGCG induced nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and promoted cytokeratin 16 (K16) expression to activate epidermal keratinocytes and robustly promoted re-epithelialization of wounds in diabetic mice. Further, EGCG demonstrated high binding affinity with Kelch-like ECH-associated protein 1 (KEAP1), thereby inhibiting KEAP1-mediated degradation of NRF2. Our findings provide important evidence that EGCG accelerates the wound healing response in diabetic mice by activating epidermal keratinocytes, thereby promoting re-epithelialization of wounds via K16/NRF2/KEAP1 signaling axis. These mechanistic insights into the protective effects of EGCG further suggest its therapeutic potential as a promising drug for treating chronic wounds in T2D.

Copaifera langsdorffii Oleoresin-Loaded Nanostructured Lipid Carrier Emulgel Improves Cutaneous Healing by Anti-Inflammatory and Re-Epithelialization Mechanisms.

The skin is essential to the integrity of the organism. The disruption of this organ promotes a wound, and the organism starts the healing to reconstruct the skin. Copaifera langsdorffii is a tree used in folk medicine to treat skin affections, with antioxidant and anti-inflammatory properties. In our study, the oleoresin of the plant was associated with nanostructured lipid carriers, aiming to evaluate the healing potential of this formulation and compare the treatment with reference drugs used in wound healing. Male Wistar rats were used to perform the excision wound model, with the macroscopic analysis of wound retraction. Skin samples were used in histological, immunohistochemical, and biochemical analyses. The results showed the wound retraction in the oleoresin-treated group, mediated by α-smooth muscle actin (α-SMA). Biochemical assays revealed the anti-inflammatory mechanism of the oleoresin-treated group, increasing interleukin-10 (IL-10) concentration and decreasing pro-inflammatory cytokines. Histopathological and immunohistochemical results showed the improvement of re-epithelialization and tissue remodeling in the Copaifera langsdorffii group, with an increase in laminin-γ2, a decrease in desmoglein-3 and an increase in collagen remodeling. These findings indicate the wound healing potential of nanostructured lipid carriers associated with Copaifera langsdorffii oleoresin in skin wounds, which can be helpful as a future alternative treatment for skin wounds.

Healing techniques for split-thickness skin grafts donor sites. Umbrella review.

OBJECTIVES: To summarize the existing evidence and provide recommendations for the most effective management of partial-thickness graft donor sites in adults, with the goals of enhancing re-epithelialization, reducing pain, and preventing infection. METHODOLOGY: Umbrella review. A systematic search was conducted encompassing databases such as Pubmed, CUIDEN, Cochrane Library, CINHAL Plus, SCOPUS, and LILACS. The search targeted systematic reviews published since 2011 that focused on examining the effectiveness of different approaches for the treatment of partial-thickness graft donor sites. Reviews with a low critical appraisal score according to AMSTAR 2 were excluded. The included reviews were evaluated using the SIGN scale to assess the level of evidence and grade the recommendations. RESULTS: Five systematic reviews with meta-analysis were incorporated in the analysis. Platelet-rich plasma and human amniotic membrane demonstrated statistically significant improvements in re-epithelialization and pain reduction when compared to the control group. Moreover, platelet-rich plasma also exhibited a decrease in wound infection rates. Recombinant human growth hormone was found to expedite the re-epithelialization process. CONCLUSIONS: Based on the findings, the use of platelet-rich plasma is recommended to enhance re-epithelialization, alleviate pain, and reduce infection in partial-thickness graft donor sites among adults. Application of human amniotic membrane is recommended to accelerate re-epithelialization and alleviate pain, while recombinant human growth hormone is suggested to expedite the overall healing time of these wounds.

Multicellular bioprinted skin facilitates human-like skin architecture in vivo.

Bioprinting is a promising alternative method to generate skin substitutes because it can replicate the structural organization of the skin into biomimetic layers in vitro. In this study, six primary human skin cell types were used to bioprint a trilayer skin construct consisting of epidermis, dermis, and hypodermis. Transplantation of the bioprinted skin with human cells onto full-thickness wounds of nu/nu mice promoted rapid vascularization and formation of epidermal rete ridges analogous to the native human epidermis, with a normal-looking extracellular matrix. Cell-specific staining confirmed the integration of the implanted cells into the regenerated skin. Using a similar approach, a 5 centimeter-by-5 centimeter bioprinted autologous porcine skin graft was transplanted onto full-thickness wounds in a porcine excisional wound model. The bioprinted skin graft improved epithelialization, reduced skin contraction, and supported normal collagen organization with reduced fibrosis. Differential gene expression demonstrated pro-remodeling protease activity in wounds transplanted with bioprinted autologous skin grafts. These results demonstrate that bioprinted skin can support skin regeneration to allow for nonfibrotic wound healing and suggest that the skin bioprinting technology may be applicable for human clinical use.

[Research progress of metal micro-battery dressings in wound repair].

To develop the dressings that can both inhibit bacterial infection and actively promote healing is of great importance for wound repair and the development of medical technology. Electrical stimulation has multiple roles in wound healing, including hemostasis, antibacterial, anti-inflammatory, guidance of cell migration, promotion of re-epithelialization, and proliferation of cells. Metal micro-battery can provide a stable source of electrical stimulation energy without an external power source. Thus, the integration of metal micro-battery with medical dressings opens up new opportunities for the wireless application of electrical stimulation in wound repair. In this review, the mechanism of the effect of electrical stimulation on wound healing is systematically presented, then recent advances in metal micro-battery dressings, including preparation methods, antibacterial performance, and healing properties are mainly introduced, and the current challenges and prospects of metal micro-battery dressings are also provided.

Use of bioelectric dressings for patients with hard-to-heal wounds: a case report.

There are many types of dressings available for the management of hard-to-heal (chronic) wounds. This case report illustrates the efficacy of bioelectric dressings in healing hard-to-heal wounds in five patients. Of the patients, four had diabetic foot ulcers (DFUs) and one had a surgical site infection. Wounds were examined using the TIMES concept and debridement was carried out if needed. Amorphous hydrogel was used as conduction fluid before the application of the bioelectric wound dressings. The wound was covered with foam dressing and crepe bandage. In this case report, among all five wounds, one wound healed completely while the other four reduced in size, with the presence of more granulation and re-epithelialisation. In this case report, bioelectric wound dressings were effective in managing infection and promoting wound healing.