Skin Wound Research Articles

Multifunctional Glycopeptide-Based Hydrogel via Dual-Modulation for the Prevention and Repair of Radiation-Induced Skin Injury.

The radiation-induced skin injury (RISI) remains a great challenge for clinical wound management and care after radiotherapy, as patients will suffer from the acute radiation injury and long-term chronic inflammatory damage during the treatment. The excessive ROS in the early acute stage and prolonged inflammatory response in the late healing process always hinder therapeutic efficiency. Herein, we developed an extracellular matrix (ECM)-mimetic multifunctional glycopeptide hydrogel (oCP@As) to promote and accelerate RISI repair via a dual-modulation strategy in different healing stages. The oCP@As hydrogel not only can form an ECM-like nanofiber structure through the Schiff base reaction but also exhibits ROS scavenging and DNA double-strand break repair abilities, which can effectively reduce the acute radiation damage. Meanwhile, the introduction of oxidized chondroitin sulfate, which is the ECM polysaccharide-like component, enables regulation of the inflammatory response by adsorption of inflammatory factors, accelerating the repair of chronic inflammatory injury. The animal experiments demonstrated that oCP@As can significantly weaken RISI symptoms, promote epidermal tissue regeneration and angiogenesis, and reduce pro-inflammatory cytokine expression. Therefore, this multifunctional glycopeptide hydrogel dressing can effectively attenuate RISI symptoms and promote RISI healing, showing great potential for clinical applications in radiotherapy protection and repair.

A Multifunctional Nanocomposite Hydrogel Delivery System Based on Dual-Loaded Liposomes for Scarless Wound Healing.

Increased inflammatory responses and oxidative stress at the wound site following skin trauma impair healing. Furthermore, skin scarring places fibroblasts under severe mechanical stress and aggravates pathological fibrosis. A novel liposomal composite hydrogel is engineered for wound microenvironment remodeling, incorporating dual-loaded liposomes into gelatin methacrylate to create a nanocomposite hydrogel. Notably, tetrahydrocurcumin (THC) and hepatocyte growth factor (HGF) are encapsulated in the hydrophobic and hydrophilic layers of liposomes, respectively. The composite hydrogel maintains porous nanoarchitecture, demonstrating sustainable THC and HGF release and enhanced mechanical properties and biocompatibility. This system effectively promotes cell proliferation and angiogenesis and attenuates apoptosis. It decreases the expression of the inflammatory factors by inhibiting the high-mobility group box /receptor for advanced glycation end product/NF-κB (HMGB1/RAGE/NF-κB)pathway and increases macrophage polarization from M1 to M2 in vitro, effectively controlling inflammatory responses. It exhibits remarkable antioxidant properties by scavenging excess reactive oxygen species and free radicals. Most importantly, it effectively prevents scar formation by restraining the transforming growth factor beta (TGF-β)/Smads pathway that downregulates associated fibrotic factors. It demonstrates strong therapeutic effects against inflammation and fibrosis in a rat skin wound model with biosafety, advancing the development of innovative hydrogel-based therapeutic delivery strategies for clinical scarless wound therapy.

Enhanced Tissue Regeneration Through Immunomodulatory Extracellular Vesicles Encapsulated in Diversified Silk-Based Injectable Hydrogels.

Mesenchymal stem cells (MSCs) immunologically trained using lipopolysaccharide (LPS) display enhanced immunomodulatory capabilities. Extracellular vesicles (EVs) derived from MSCs are widely used in regenerative medicine owing to their bioactive properties without the drawbacks of cell therapy. However, it remains unclear whether EVs derived from LPS-stimulated (trained) MSCs (L-EVs) inherit the enhanced reparative potential from their parent cells. Thus, this study first aims to explore the effect of immunological training on the bioactivity of L-EVs. LPS-trained bone marrow-derived MSCs (BMSCs) secrete more EVs, and these EVs significantly promote M2 macrophage polarization. Subsequently, hydrogel systems based on thixotropic injectable silk fibroin are prepared for in vivo EV delivery. These hydrogels have controllable gelation time and exhibit outstanding reparative effects on rat skin wounds and alveolar bone defects. Finally, it is revealed that L-EVs promote M2 macrophage polarization by inhibiting the nuclear translocation of PKM2. Overall, this study shows that the immunological training of BMSCs effectively improves the therapeutic effects of their EVs and provides a convenient and diversified EV delivery strategy using an injectable silk fibroin hydrogel. This strategy has broad clinical application prospects for tissue regeneration.

Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1G93A mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1G93A mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19+ B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1G93A mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1G93A mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.

Efficacy of MSC-derived small extracellular vesicles in treating type II diabetic cutaneous wounds: a systematic review and meta-analysis of animal models

BackgroundSmall extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) have emerged as a promising therapy for treating type II diabetic cutaneous wounds. Currently, the evidence supporting the use of MSC-sEVs for treating diabetic skin wounds remains inconclusive and is limited to preclinical studies. To facilitate the clinical translation of cell-free therapy, conducting a comprehensive systematic review of preclinical studies assessing the efficacy of MSC-sEVs is imperative.MethodsA systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library databases until June 14, 2023, to identify studies that met our pre-established inclusion criteria. The outcome indicators comprised wound closure rate (primary outcome), neovascular density, re-epithelialization rate, collagen deposition, and inflammatory factors (secondary Outcomes). A fixed-effects model was employed in instances of low heterogeneity (I2<50%), while a random-effects model was utilized for high heterogeneity (I2≥50%). The risk of bias in animal studies was assessed using the SYRCLE tool.ResultsTwenty-one studies were included in this meta-analysis. Compared with the control group, MSC-sEVs were found to significantly facilitate the healing of cutaneous wounds in type II diabetic patients (standardized mean difference [SMD]=3.16, 95% confidence interval [CI]: 2.65 to 3.66, P<0.00001, I2 = 39%).ConclusionsAccording to the meta-analysis of preclinical studies, MSC-sEVs show promising applications in promoting type II diabetic wound healing. As a result, translating these findings into clinical applications appears warranted.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023375467.

Rab10-CAV1 mediated intraluminal vesicle transport to migrasomes

Migrasomes, vesicular organelles generated on the retraction fibers of migrating cells, play a crucial role in migracytosis, mediating intercellular communication. The cargoes determine the functional specificity of migrasomes. Migrasomes harbor numerous intraluminal vesicles, a pivotal component of their cargoes. The mechanism underlying the transportation of these intraluminal vesicles to the migrasomes remains enigmatic. In this study, we identified that Rab10 and Caveolin-1 (CAV1) mark the intraluminal vesicles in migrasomes. Transport of Rab10-CAV1 vesicles to migrasomes required the motor protein Myosin Va and adaptor proteins RILPL2. Notably, the phosphorylation of Rab10 by the kinase LRRK2 regulated this process. Moreover, CSF-1 can be transported to migrasomes through this mechanism, subsequently fostering monocyte-macrophage differentiation in skin wound healing, which served as a proof of the physiological importance of this transporting mechanism.

Effectiveness of minimally invasive treatment of hallux valgus with small incision external articular osteotomy

To compare the effectiveness of small incision external articular minimally invasive osteotomy and traditional Chevron osteotomy in the treatment of hallux valgus. A retrospective analysis was conducted on the clinical data of 58 patients (58 feet) with hallux valgus who were admitted between April 2019 and June 2022 and met the selection criteria. Among them, 28 cases were treated with small incision external articular minimally invasive osteotomy (minimally invasive group), and 30 cases were treated with traditional Chevron osteotomy (traditional group). There was no significant difference in baseline data such as age, gender, disease duration, Mann classification, and preoperative inter metatarsal angle (IMA), hallux valgus angle (HVA), distal metatarsal articular angle (DMAA), forefoot width, tibial sesamoid position (TSP) score, American Orthopaedic Foot and Ankle Society (AOFAS) forefoot score, visual analogue scale (VAS) score, psychological score (SF-12 MCS score) and physiological score (SF-12 PCS score) of short-form 12 health survey scale, and range of motion (ROM) of metatarsophalangeal joint between the two groups ( P>0.05). The incision length, operation time, intraoperative blood loss, intraoperative fluoroscopy frequency, weight-bearing walking time, fracture healing time, and incidence of complications were recorded and compared between the two groups; as well as the changes of imaging indexes at last follow-up, and the clinical function score and ROM of metatarsophalangeal joint before operation, at 6 weeks after operation, and at last follow-up. All patients were followed up 11-31 months, with an average of 22 months. The incision length and intraoperative blood loss in the minimally invasive group were significantly less than those in the traditional group ( P<0.05), and the intraoperative fluoroscopy frequency and operation time in the minimally invasive group were significantly more than those in the traditional group ( P<0.05); but no significant difference was found in weight-bearing walking time and fracture healing time between the two groups ( P>0.05). There was 1 case of skin injury in the minimally invasive group and 3 cases of poor incision healing in the traditional group; all patients had good healing at the osteotomy site, and no complication such as infection, nerve injury, or metatarsal head necrosis occurred. At last follow-up, the imaging indexes of the two groups significantly improved when compared with those before operation ( P<0.05). The changes of DMAA and TSP score in the minimally invasive group were significantly better than those in the traditional group ( P<0.05), and there was no significant difference in the changes of IMA, HVA, and forefoot width between the two groups ( P>0.05). The clinical scores and ROM of metatarsophalangeal joint significantly improved in the two groups at 6 weeks after operation and at last follow-up when compared with preoperative ones ( P<0.05), and the indicators in the minimally invasive group were significantly better than those in the traditional group ( P<0.05). Compared with traditional Chevron osteotomy, small incision external articular minimally invasive osteotomy can effectively improve HVA, IMA, and forefoot width, correct foot deformities, and has less trauma. It can better correct the first metatarsal pronation deformity and restore the anatomical position of the sesamoid bone, resulting in better effectiveness.

Wound Healing Promotion via Release of Therapeutic Metallic Ions from Phosphate Glass Fibers: An In Vitro and Ex Vivo Study.

Biomaterials capable of promoting wound healing and preventing infections remain in great demand to address the global unmet need for the treatment of chronic wounds. Phosphate-based glasses (PG) have shown potential as bioresorbable materials capable of inducing tissue regeneration, while being replaced by regenerated tissue and releasing therapeutic species. In this work, phosphate-glass-based fibers (PGF) in the system P2O5-CaO-Na2O added with 1, 2, 4, 6, and 10 mol % of the therapeutic metallic ions (TMI) Ag+, Zn2+, and Fe3+ were manufactured via electrospinning of coacervate gels. Coacervation is a sustainable, cost-effective, water-based method to produce PG. All TMI are effective in promoting wound closure (re-epithelialization) in living human skin ex vivo, where the best-performing system is PGF containing Ag+. In particular, PGF with ≥4 mol % of Ag+ is capable of promoting 84% wound closure over 48 h. These results are confirmed by scratch test migration assays, with the PGF-Ag systems containing ≥6 mol % of Ag+, demonstrating significant wound closure enhancement (up to 72%) after 24 h. The PGF-Ag systems are also the most effective in terms of antibacterial activity against both the Gram-positive Staphylococcus aureus and the Gram-negative Escherichia coli. PGF doped with Zn2+ shows antibacterial activity only against S. aureus in the systems containing Zn2+ ≥ 10 mol %. In addition, PGF doped with Fe3+ rapidly accelerates ex vivo healing in patient chronic wound skin (>30% in 48 h), demonstrating the utility of doped PGF as a potential therapeutic strategy to treat chronic wounds.

Electrical Stimulating Redox Membrane Incorporated with PVA/Gelatin Nanofiber for Diabetic Wound Healing.

Chronic wounds adversely affect the quality of life. Although electrical stimulation has been utilized to treat chronic wounds, there are still limitations to practicing it due to the complicated power system. Herein, an electrostimulating membrane incorporated with electrospun nanofiber (M-sheet) to treat diabetic wounds is developed. Through the screen printing method, the various alternate patterns of both Zn and AgCl on a polyurethane substrate, generating redox-mediated electrical fields are introduced. The antibacterial ability of the patterned membrane against both E. coli and S. aureus is confirmed. Furthermore, the poly(vinyl alcohol) (PVA)/gelatin electrospun fiber is incorporated into the patterned membrane to enhance biocompatibility and maintain the wet condition in the wound environment. The M-sheet can improve cell proliferation and migration in vitro and has an immune regulatory effect by inducing the polarization of macrophage to the M2 phenotype. Finally, when applied to a diabetic skin wound model, the M-sheet displays an accelerated wound healing rate and enhances re-epithelialization, collagen synthesis, and angiogenesis. It suggests that the M-sheet is a simple and portable system for the spontaneous generation of electrical stimulation and has great potential to be used in the practical wound and other tissue engineering applications.

Magneto-responsive biocomposites in wound healing: from characteristics to functions.

The number of patients with non-healing wounds continuously increases, and has become a prominent societal issue that imposes a heavy burden on both patients and the entire healthcare system. Although traditional dressings play an important role in wound healing, the complexity and diversity of the healing process pose serious challenges in this field. Magneto-responsive biocomposites, with their excellent biocompatibility, remote spatiotemporal controllability, and unique convenience, demonstrate enticing advantages in the field of wound dressings. However, current research on magneto-responsive biocomposites as wound dressings lacks comprehensive and in-depth reviews, which to some extent, restricts the deeper understanding and further development of this field. Based on this, this paper reviews the latest advances in magnetic responsive wound dressings for wound healing. First, we review the process of skin wound healing and parameters for assessing repair progress. Then, we systematically discuss the preparation strategies and unique characteristics of magneto-responsive biocomposites, focusing on magneto-induced orientation, magneto-induced mechanical stimulation, and magnetocaloric effect. Subsequently, this review elaborates the multiple mechanisms of magneto-responsive biocomposites in promoting wound healing, including regulating cell behavior, enhancing electrical signal, controlling drug release, and accelerating tissue reconstruction. Finally, we further propose the development direction and future challenges of magnetic responsive biomaterials as wound dressings in clinical application.

Towards the development of sensation-enabled skin substitutes.

Recent advances in cell and biofabrication technologies have contributed to the development of complex human organs. In particular, several skin substitutes are being generated using tissue engineering and regenerative medicine (TERM) technologies. However, recent studies mainly focus on the restoration of the dermis and epidermis layers rather than the regeneration of a fully functional innervated skin organ. Innervation is a critical step in functional tissue repair which has been overlooked in the current TERM studies. In the current study, we highlight the importance of sensation in the skin as the largest sensory organ in the human body. In large non-healing skin wounds, the skin sensation is severely diminished or completely lost and ultimately lead to chronic pain and wound healing process interruption. Current therapeutics for restoring skin sensation after trauma are limited. Recent regenerative medicine-based studies could successfully induce neural networks in skin substitutes, but the effectiveness of these technologies in enhancing sensory capability needs further investigation.

Integrating Bioactive Graded Hydrogel with Radially Aligned Nanofibers to Dynamically Manipulate Wound Healing Process.

Skin wound healing is a complex process that requires appropriate treatment and management. Using a single scaffold to dynamically manipulate angiogenesis, cell migration and proliferation, and tissue reconstruction during skin wound healing is a great challenge. We developed a hybrid scaffold platform that integrates the spatiotemporal delivery of bioactive cues with topographical cues to dynamically manipulate the wound-healing process. The scaffold comprised gelatin methacryloyl hydrogels and electrospun poly(ε-caprolactone)/gelatin nanofibers. The hydrogels had graded cross-linking densities and were loaded with two different functional bioactive peptides. The nanofibers comprised a radially aligned nanofiber array layer and a layer of random fibers. During the early stages of wound healing, the KLTWQELYQLKYKGI peptide, which mimics vascular endothelial growth factor, was released from the inner layer of the hydrogel to accelerate angiogenesis. During the later stages of wound healing, the IKVAVS peptide, which promotes cell migration, synergized with the radially aligned nanofiber membrane to promote cell migration, while the nanofiber membrane also supported further cell proliferation. In an in vivo rat skin wound-healing model, the hybrid scaffold significantly accelerated wound healing and collagen deposition, and the ratio of type I to type III collagen at the wound site resembled that of normal skin. The prepared scaffold dynamically regulated the skin tissue regeneration process in stages to achieve rapid wound repair with clinical application potential, providing a strategy for skin wound repair.

Fast Self-Healing Hyaluronic Acid Hydrogel with a Double-Dynamic Network for Skin Wound Repair.

Developing extracellular matrix-derived hydrogel with a fast self-healing capacity to provide a sustainable moist environment able to accelerate wound healing is highly desired for full-thickness skin wound repair. In this study, a fast self-healing hyaluronic acid hydrogel with a dual dynamic network was constructed through a primary reversible acylhydrazone bond formed between aldehyde-modified hyaluronic acid, 3,3'-dithiobis (propionyl hydrazide) (DTP), and secondary dynamic ionic interactions between κ-carrageenan (KC) and K+. Because of the presence of various dynamic covalent bonds such as the acylhydrazone bond, disulfide bond, and noncovalent bonds including hydrogen bonding and ionic interactions, as well as the notable thermoreversible nature of KC, the resultant hydrogel could be self-healed rapidly within 30 min under physiological temperature with a self-healing efficiency of 100%, which was significantly better than other hyaluronic acid hydrogels, as reported previously. Besides, the hydrogel displayed excellent cytocompatibility. According to this study, the hydrogel was administered into the wounds and achieved a superior performance of promoting full-thickness skin wound healing by increasing granulation tissue formation, deposition of collagen as well as the acceleration of re-epithelialization and neovascularization, compared to commercial products, e.g., gauze and 3 M hydrocolloid. We also anticipate that this strategy of double-dynamic network cross-linking can be adopted to fabricate self-healing materials for multiple applications.

Efficacy of sodium hypochlorite in overcoming antimicrobial resistance and eradicating biofilms in clinical pathogens from pressure ulcers

Sodium hypochlorite (NaOCl) is widely recognized for its broad-spectrum antimicrobial efficacy in skin wound care. This study investigates the effectiveness of NaOCl against a range of bacterial and fungal isolates from pressure ulcer (PU) patients.We analyzed 20 bacterial isolates from PU patients, comprising carbapenem-resistant Klebsiella pneumoniae (CRKP), multidrug-resistant Acinetobacter baumannii (MDRAB), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), along with 5 Candida albicans isolates. Antibiotic resistance profiles were determined using standard susceptibility testing. Whole-genome sequencing (WGS) was employed to identify antimicrobial resistance genes (ARGs) and disinfectant resistance genes (DRGs). Genetic determinants of biofilm formation were also assessed. The antimicrobial activity of NaOCl was evaluated by determining the minimum inhibitory concentration (MIC) and the minimal biofilm eradication concentration (MBEC) for both planktonic and biofilm-associated cells.CRKP and MDRAB showed resistance to fluoroquinolones and carbapenems, while MRSA exhibited resistance to β-lactams and levofloxacin. MSSA displayed a comparatively lower resistance profile. WGS identified significant numbers of ARGs in CRKP and MDRAB, with fewer DRGs compared to MRSA and MSSA. All isolates possessed genes associated with fimbriae production and adhesion, correlating with pronounced biofilm biomass production. NaOCl demonstrated substantial antimicrobial activity against both planktonic cells and biofilms. The MIC90 for planktonic bacterial cells was 0.125 mg/mL, and the MBEC90 ranged from 0.225 to 0.5 mg/mL. For planktonic C. albicans, the MIC90 was 0.150 mg/mL, and the MBEC90 was 0.250 mg/mL.These results highlight the challenge in treating biofilm-associated infections and underscore the potential of NaOCl as a robust antimicrobial agent against difficult-to-treat biofilm infections at concentrations lower than those typically found in commercial disinfectants.

METTL3-mediated NDUFB5 m6A modification promotes cell migration and mitochondrial respiration to promote the wound healing of diabetic foot ulcer

BackgroundDiabetic foot ulcer (DFU) is the most devastating complication of diabetes mellitus (DM) and plays a major role in disability and death in DM patients. NADH: ubiquinone oxidoreductase subunit B5 (NDUFB5) plays an important role in maintaining mitochondrial respiration, but whether it is involved in regulating the progression of advanced glycation end products (AGEs)-mediated DFU is still unclear.MethodsFirstly, the role of AGEs on cell viability, migration, and mitochondrial respiration in human umbilical vein endothelial cells (HUVECs) was explored in vitro. Next, NDUFB5 expression was detected in human samples and AGEs-treated HUVECs, and NDUFB5’s effect on AGEs-induced HUVECs injury and skin wound in diabetic mice was further clarified. In addition, the role of m6A modification mediated by methyltransferase-like 3 (METTL3) in regulating NDUFB5 expression and AGEs-induced HUVECs injury was investigated.ResultsNDUFB5 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs, whereas mitochondrial fusion promoter M1 facilitated cell viability, migration, and mitochondrial oxiadative respiration in NDUFB5 knockdown HUVECs. Meanwhile, NDUFB5 promotes skin wound healing in diabetic mice. Besides, METTL3-mediated m6A modification and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) enhanced NDUFB5 expression in HUVECs. Furthermore, METTL3 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs by increasing NDUFB5.ConclusionMETTL3-mediated NDUFB5 m6A modification inhibits AGEs-induced cell injury in HUVECs. METTL3 and NDUFB5 might serve as potential targets for DFU therapy in the future.

METTL3-mediated NDUFB5 m6A modification promotes cell migration and mitochondrial respiration to promote the wound healing of diabetic foot ulcer

BackgroundDiabetic foot ulcer (DFU) is the most devastating complication of diabetes mellitus (DM) and plays a major role in disability and death in DM patients. NADH: ubiquinone oxidoreductase subunit B5 (NDUFB5) plays an important role in maintaining mitochondrial respiration, but whether it is involved in regulating the progression of advanced glycation end products (AGEs)-mediated DFU is still unclear.MethodsFirstly, the role of AGEs on cell viability, migration, and mitochondrial respiration in human umbilical vein endothelial cells (HUVECs) was explored in vitro. Next, NDUFB5 expression was detected in human samples and AGEs-treated HUVECs, and NDUFB5’s effect on AGEs-induced HUVECs injury and skin wound in diabetic mice was further clarified. In addition, the role of m6A modification mediated by methyltransferase-like 3 (METTL3) in regulating NDUFB5 expression and AGEs-induced HUVECs injury was investigated.ResultsNDUFB5 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs, whereas mitochondrial fusion promoter M1 facilitated cell viability, migration, and mitochondrial oxiadative respiration in NDUFB5 knockdown HUVECs. Meanwhile, NDUFB5 promotes skin wound healing in diabetic mice. Besides, METTL3-mediated m6A modification and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) enhanced NDUFB5 expression in HUVECs. Furthermore, METTL3 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs by increasing NDUFB5.ConclusionMETTL3-mediated NDUFB5 m6A modification inhibits AGEs-induced cell injury in HUVECs. METTL3 and NDUFB5 might serve as potential targets for DFU therapy in the future.

Comparative Study of Unfractionated Heparins and Low Molecular Weight Heparin on Skin Wound Repair

Aims: Heparin (HP) has aroused interest in the treatment of skin wounds. The HP extraction sources and the chemical diversity of its structural chain result in different clinical responses. In this study, a comparison was made among the effects of unfractionated heparin from bovine (bovHP) and swine (swi.HP) sources and low molecular weight heparin (LMWH) on skin lesions treatment. Study Design: Wounds were induced on the back of Swiss mice using a punch. Then, the wounds were treated with heparins for 3 and 7 days. Place and Duration of Study: Institute of Biomedical Sciences and Animal Breeding Network and Rodents of the Federal University of Uberlândia, between April 2018 and February 2020. Methodology: Wound closure was performed with a digital caliper. The inflammatory infiltrate was assessed by the activity of neutrophils and macrophages. Angiogenesis was measured by quantifying blood vessels and measuring hemoglobin. While fibrogenesis was assessed by picrosirius red staining. Results: None of the heparins had a healing effect. Swi.HP showed delay in wound closure and intensification of the inflammatory process compared to bov.HP. Swine and bovine heparins showed pro-angiogenic activity, although this did not differ between them. Difference between the groups of heparins was observed in relation to the deposition and organization of collagen fibers, with a reduction in fibrogenesis in wounds of the LMWH group compared to the other heparins, especially bov.HP. A better fibrogenic activity was observed for bov.HP. Conclusion: Thus, we conclude that the source of the heparin used should be considered, as its pharmacological response for wound treatment is quite diverse. Although none of the heparins was able to accelerate wound closure, bov.HP had an anti-inflammatory and pro- fibrogenic effect compared to the other heparins and therefore showed the best response in this experimental model.

OxInflammatory Responses in the Wound Healing Process: A Systematic Review

Significant sums are spent every year to find effective treatments to control inflammation and speed up the repair of damaged skin. This study investigated the main mechanisms involved in the skin wound cure. Consequently, it offered guidance to develop new therapies to control OxInflammation and infection and decrease functional loss and cost issues. This systematic review was conducted using the PRISMA guidelines, with a structured search in the MEDLINE (PubMed), Scopus, and Web of Science databases, analyzing 23 original studies. Bias analysis and study quality were assessed using the SYRCLE tool (Prospero number is CRD262 936). Our results highlight the activation of membrane receptors (IFN-δ, TNF-α, toll-like) in phagocytes, especially macrophages, during early wound healing. The STAT1, IP3, and NF-kβ pathways are positively regulated, while Ca2+ mobilization correlates with ROS production and NLRP3 inflammasome activation. This pathway activation leads to the proteolytic cleavage of caspase-1, releasing IL-1β and IL-18, which are responsible for immune modulation and vasodilation. Mediators such as IL-1, iNOS, TNF-α, and TGF-β are released, influencing pro- and anti-inflammatory cascades, increasing ROS levels, and inducing the oxidation of lipids, proteins, and DNA. During healing, the respiratory burst depletes antioxidant defenses (SOD, CAT, GST), creating a pro-oxidative environment. The IFN-δ pathway, ROS production, and inflammatory markers establish a positive feedback loop, recruiting more polymorphonuclear cells and reinforcing the positive interaction between oxidative stress and inflammation. This process is crucial because, in the immune system, the vicious positive cycle between ROS, the oxidative environment, and, above all, the activation of the NLRP3 inflammasome inappropriately triggers hypoxia, increases ROS levels, activates pro-inflammatory cytokines and inhibits the antioxidant action and resolution of anti-inflammatory cytokines, contributing to the evolution of chronic inflammation and tissue damage.

Shifts in keratin isoform expression activate motility signals during wound healing.

Keratin intermediate filaments confer structural stability to epithelial tissues, but the reason this simple mechanical function requires a protein family with 54 isoforms is not understood. During skin wound healing, a shift in keratin isoform expression alters the composition of keratin filaments. If and how this change modulates cellular functions that support epidermal remodeling remains unclear. We report an unexpected effect of keratin isoform variation on kinase signal transduction. Increased expression of wound-associated keratin 6A, but not of steady-state keratin 5, potentiated keratinocyte migration and wound closure without compromising mechanical stability by activating myosin motors to increase contractile force generation. These results substantially expand the functional repertoire of intermediate filaments from their canonical role as mechanical scaffolds to include roles as isoform-tuned signaling scaffolds that organize signal transduction cascades in space and time to influence epithelial cell state.

Antinociceptive and wound healing effects of a commercial formulation of lidocaine, bupivacaine, adrenaline and cetrimide applied topically to superficial skin wounds in horses.

Post-traumatic distal limb wounds cause discomfort and heal gradually by second intention. The topical application of Tri-Solfen (lidocaine hydrochloride, bupivacaine hydrochloride, adrenaline acid tartrate and cetrimide [LBAC]) produces effective postsurgical cutaneous analgesia in lambs, calves and piglets; however, its effect on wounds in horses is unknown. The antinociceptive effect, measured by mechanical threshold (MT), and the wound healing impacts of LBAC compared with saline were investigated on surgically created 20 × 20 mm distal limb wounds in 10 horses. Treatment was applied once daily for 7 days following wounding on day 0. Mechanical thresholds were measured after treatment on days 1, 2 and 3. Healing was observed for 25 days. The topical application of LBAC immediately following wounding and its reapplication 24 hours later increased the average MT on the first post-traumatic day by 3 Newtons. However, no antinociceptive benefit was observed on days 2 or 3. Treatment with LBAC did not adversely affect wound healing when compared with saline. Methodological differences preclude absolute MT comparisons between studies. The experimental design did not include a model of contaminated or naturally occurring wounds. LBAC may provide an early antinociceptive benefit when applied to uncontaminated surgically created wounds without compromising healing.