Despite decades of research, impaired extremity wound healing in type 2 diabetes remains a significant driver of patient morbidity, mortality, and health care costs. Advances in surgical and medical therapies, including the advent of endovascular interventions for peripheral artery disease and topical therapies developed to promote wound healing, have not reduced the frequency of lower leg amputations for nonhealing wounds in type 2 diabetes. This brief report is aimed at reviewing the roles of various cell types in tissue repair and summarizing the known dysfunctions of these cell types in diabetic foot ulcers. Recent advances in our understanding of the epigenetic regulation in immune cells identified to be altered in type 2 diabetes are summarized, and particular attention is paid to the developing research defining the epigenetic regulation of structural cells, including keratinocytes, fibroblasts, and endothelial cells. Gaps in knowledge are highlighted, and potential future directions are suggested based on the current state of the field.

Heterotopic ossification (HO) is characterized by the abnormal growth of ectopic bone in non-skeletal soft tissues through a fibrotic pathway and is a frequent complication in a wide variety of musculoskeletal injuries. We have previously demonstrated that TGFβ levels are elevated in the soft tissues following extremity injuries. Since TGFβ mediates the initial inflammatory and wound-healing response in the traumatized muscle bed, we hypothesized that targeted inhibition of the TGFβ pathway may be able to abrogate the unbalanced fibrotic phenotype and bone-forming response observed in post-traumatic HO. Primary mesenchymal progenitor cells (MPCs) harvested from debrided traumatized human muscle tissue were used in this study. After treatment with TGFβ inhibitors (SB431542, Galunisertib/LY2157299, Halofuginone, and SIS3) cell proliferation/survival, fibrotic formation, osteogenic induction, gene expression, and phosphorylation of SMAD2/3 were assessed. In vivo studies were performed with a Sprague-Dawley rat blast model treated with the TGFβ inhibitors. The treatment effects on the rat tissues were investigated by radiographs, histology, and gene expression analyses. Primary MPCs treated with TGFβ had a significant increase in the number of fibrotic nodules compared to the control, while TGFβ inhibitors that directly block the TGFβ extracellular receptor had the greatest effect on reducing the number of fibrotic nodules and significantly reducing the expression of fibrotic genes. In vivo studies demonstrated a trend towards a lower extent of HO formation by radiographic analysis up to 4 months after injury when animals were treated with the TGFβ inhibitors SB431542, Halofuginone and SIS3. Altogether, our results suggest that targeted inhibition of the TGFβ pathway may be a useful therapeutic strategy for post-traumatic HO patients.

Chronic fibrosis replaces functional organ tissue with scar tissue by overproduction of a thick and stiff extracellular matrix. Bladder fibrosis decreases bladder compliance, ultimately resulting in overactive bladder. The phenoconversion of fibroblasts into myofibroblasts is the defining feature of fibrosis. Recently, regionally distinct populations of bladder platelet-derived growth factor receptor alpha positive (PDGFRα+) cells were identified as fibroblasts. Because of this heterogeneity, the identity of the bladder fibroblast cells that undergo phenotypic conversion into myofibroblasts is not clear. The current study utilized cyclophosphamide (CYP)-induced bladder inflammation to identify and characterize bladder PDGFRα+ cells that become myofibroblasts. We found that suburothelial PDGFRα+ cells and detrusor PDGFRα+ cells display different gene expression profiles. Suburothelial PDGFRα+ cells are more abundant than detrusor PDGFRα+ cells and express higher levels of fibrosis-related genes. CYP-treatment increased the number of suburothelial PDGFRα+ cells, increased Pdgfra, Col1a1, and Fn1 transcription in suburothelial PDGFRα+ cells, and increased α-smooth muscle actin, collagen, and fibronectin protein expression. CYP-treatment likely activated TNF-α and TGF-ß pathways, as indicated by nuclear translocation of SMAD2, SMAD3, and NFκB. In conclusion, we identify suburothelial PDGFRα+ cells as the fibroblast population which convert into myofibroblasts via activation of TNF-α and TGF-ß signaling pathways, due to bladder inflammation.

Nanofibers fabricated from various materials such as polymers, carbon, and semiconductors have been widely used for wound healing and tissue engineering applications due to their excellent nontoxic, biocompatible, and biodegradable properties. Nanofibers with a diameter in the nanometer range possess a larger surface area per unit mass permitting easier addition of surface functionalities and release of biotherapeutics incorporated compared with conventional polymeric microfibers. Henceforth, nanofibers are a choice for fabricating scaffolds for the management of wound healing. Nanofibrous scaffolds have emerged as a promising method for fabricating wound dressings since they mimic the fibrous dermal extracellular matrix milieu that offers structural support for wound healing and functional signals for guiding tissue regeneration. Cellulose-based nanofibers have gained significant attention among researchers in the fabrication of on-site biodegradable scaffolds fortified with biotherapeutics in the management of wound healing. Cellulose is a linear, stereoregular insoluble polymer built from repeated units of d-glucopyranose linked with 1,4-β glycoside bonds with a complex and multilevel supramolecular architecture. Cellulose is a choice and has been used by various researchers due to its solubility in many solvents and its capacity for self-assembly into nanofibers, facilitating the mimicry of the natural extracellular matrix fibrous architecture and promoting substantial water retention. It is also abundant and demonstrates low immunogenicity in humans due to its nonanimal origins. To this end, cellulose-based nanofibers have been studied for protein delivery, antibacterial activity, and biosensor applications, among others. Taken together, this review delves into an update on cellulose-based nanofibers fused with bioactive compounds that have not been explored considerably in the past few years.

The skin plays a crucial role in the body's homeostasis through its thermoregulation functions, metabolic activity, and, mainly, its barrier function. Once this system has its homeostasis disturbed, through the promotion of tissue discontinuity, an injury happens and a restoration process starts. Different products can be used to promote, accelerate, or stimulate the healing process, such as hydrogels, emulsions, and ointments (main conventional formulations). Despite the historical use and wide market and consumer acceptance, new systems emerged for wound management with the main challenge to overcome conventional form limitations, in which nanosystems are found, mainly nanobased emulsion forms (nano- and microemulsions, NE and ME). Here, we discuss the skin function and wound healing process, highlighting the cellular and molecular processes, the different wound classifications, and factors that affect physiological healing. We also investigated the recent patents (2012-2023) filed at the United States Patent and Trademark Office, where we found few patents for conventional forms (hydrogels = 5; emulsions = 4; ointments = 6) but a larger number of patents for nanobased emulsions filed in this time (NE = 638; ME = 4,072). Furthermore, we address the use of nanobased emulsions (NE and ME) and their particularities, differences, and application in wound treatment. This work also discusses the challenges, bottlenecks, and regulatory framework for nanosystems, industrial, academic, and government interest in nanotechnology, and future perspectives about this key factor for the nanosystems market and consumer acceptance.

While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter. The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.

Bone defects, whether caused by trauma, cancer, infectious diseases, or surgery, can significantly impair people's quality of life. Although autografts are the gold standard for treating bone defects, they often fall short in adequately forming bone tissue. The field of bone tissue engineering has made strides in using scaffolds with various biomaterials, stem cells, and growth factors to enhance bone healing. However, some biological structures do not yield satisfactory therapeutic outcomes for new bone formation. Recent studies have shed light on the crucial role of immunomodulation, specifically the interaction between the implanted scaffold and host immune systems, in bone regeneration. Immune cells, particularly macrophages, are pivotal in the inflammatory response, angiogenesis, and osteogenesis. This review delves into the immune system's mechanism toward foreign bodies and the recent advancements in scaffolds' physical and biological properties that foster bone regeneration by modulating macrophage polarization to an anti-inflammatory phenotype and enhancing the osteoimmune microenvironment.

The escalating prevalence of tissue damage and its associated complications has elicited global apprehension. While nanomaterial-based wound healing exhibits significant potential in terms of curbing infections and surpassing conventional methods, unresolved concerns regarding nanomaterial controllability and precision remain unresolved, jeopardizing its practical applications. In recent years, a unique strategy for creating gas-releasing nanomaterials for wound repair has been proposed, involving the creation of gas-releasing nanomaterials to facilitate wound repair by generating gas donor moieties. The operational spatiotemporal responsiveness and broad-spectrum antibacterial properties of these gases, combined with their inability to generate bacterial resistance like traditional antibiotics, establish their efficacy in addressing chronic non-healing wounds, specifically diabetic foot ulcers (DFUs). In this review, we delve into the intricacies of wound healing process, emphasizing the chemical design, functionality, bactericidal activity, and potential of gas-release materials, encompassing NO, CO, H2S, O2, CO2, and H2, for effective wound healing. Furthermore, we explore the advancements in synergistic therapy utilizing these gases, aiming to enhance our overall comprehension of this field. The insights gleaned from this review will undoubtedly aid researchers and developers in the creation of promising gas-releasing nanomaterials, thus propelling efficient wound healing in the future.

The dynamic, complex process of cutaneous wound healing is required to restore skin integrity following an injury. This intricate process consists of four sequential and overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Hemostasis immediately begins to function in response to vascular injury, forming a clot that stops the bleeding. To fight infection and remove debris, immune cells are enlisted during the inflammatory phase. Angiogenesis, re-epithelialization, and the creation of new tissue are all components of proliferation, whereas tissue maturation and scarring are the outcomes of remodeling. Chronic wounds, like those found in diabetic ulcers, frequently stay in a state of chronic inflammation because they are unable to go through these stages in a coordinated manner. The important regulatory roles that microRNAs (miRNAs) play in both normal and pathological wound healing have been highlighted by recent investigations. The miRNAs, small non-coding RNAs, modulate gene expression post-transcriptionally, profoundly impacting cellular functions. During the inflammatory phase, miRNAs control pro- and anti-inflammatory cytokines, as well as the activity of immune cells such as neutrophils and macrophages. Additionally, miRNAs are essential components of signaling networks related to inflammation, such as the toll-like receptor (TLR), nuclear factor kappa B (NF-kB), and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. Some miRNAs have been discovered to either increase or alleviate inflammatory reactions, indicating their potential as therapeutic targets. Other miRNAs aid in angiogenesis by promoting the development of new blood vessels, which are essential for providing oxygen and nutrients to the healing tissue. They also affect keratinocyte migration and proliferation during the re-epithelialization phase, which involves growing new epithelial cells over the lesion. Another function of miRNAs is that they control the deposition of extracellular matrix (ECM) and the creation of scars during the remodeling phase. The abnormal expression of miRNAs in chronic wounds has led to the exploration of miRNA-based treatments. With a focus on resistant instances such as diabetic wounds, these therapeutic techniques seek to improve wound healing results by correcting the dysregulated miRNA expression.

Hypertrophic scars (HTSs) result from aberrant wound healing processes, leading to raised, thickened tissue with functional discomfort and cosmetic concerns. Current treatments, including corticosteroid injections and laser therapy, have limitations. Stromal vascular fraction (SVF) therapy and CO2 laser treatment offer promising avenues, with SVF therapy showing regenerative potential and CO2 laser therapy promoting precise tissue removal and wound healing. This study aims to investigate the combined application of SVF therapy and CO2 laser treatment for HTS, aiming to enhance treatment efficacy, tissue remodeling, and aesthetic outcomes, ultimately improving patient satisfaction in HTS management.

PubMed, Scopus, Embase, and Web of Science databases have been searched for relevant studies. The "R" software (version 4.3.1) along with the "tidyverse" and "meta" statistical packages utilized to analyze data related to the efficiency of this combined method. A random-effects model was fitted to the data. For each study, continuous outcomes were pooled by calculating the standardized mean difference, along with their 95% confidence intervals. The assessment of heterogeneity utilized the I2 and chi-squared tests, applying the random effect model.

Six articles fulfilled our inclusion criteria and were included in our review. Results from the pooled analysis of Vancouver Scar Scale (VSS) scores across three included studies indicated a significant impact of the SVF+CO2 method on VSS scores post-treatment (SMD=-3.0144; 95% CI:-4.3706 to -1.6583, p<0.0001). However, analysis of transepidermal water loss levels before and after treatment showed no significant difference (SMD=-2.7603; 95% CI: -6.8729 to 1.3522; p=0.1883). Comparatively, in a pooled analysis of two studies, the combined SVF+CO2 method demonstrated superior efficacy in VSS scores compared to other methods (SMD= -1.3573; 95% CI: -2.2475 to -0.4672, p = 0.0028), with moderate heterogeneity across studies (I^2=23.0%, p = 0.2545).

The combined application of SVF and CO2 laser treatment shows significant promise in improving hypertrophic scars' appearance and texture. The SVF+CO2 method demonstrates superior efficacy compared to other modalities, suggesting its potential as a valuable therapeutic approach for hypertrophic scar management.

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Chronic wounds significantly contribute to disability and affect the mortality rate in diabetic patients. In addition, pressure ulcers, diabetic foot ulcers, arterial ulcers, and venous ulcers pose a significant health burden due to their associated morbidity and death. The complex healing process, environmental factors, and genetic factors have been identified as the rate-limiting stages of chronic wound healing. Changes in temperature, moisture content, mechanical strain, and genetics can result in slow wound healing, increased susceptibility to bacterial infections, and poor matrix remodelling. These obstacles can be addressed with natural biomaterials exhibiting antimicrobial, collagen synthesis, and granulation tissue formation properties. Recently, silk proteins have gained significant attention as a natural biomaterial owing to good biocompatibility, biodegradability, reduced immunogenicity, ease of sterilization, and promote the wound healing process. The silk components such as sericin and fibroin in combination with nano(platforms) effectively promote wound repair. This review emphasises the potential of sericin and fibroin when combined with nano(platforms) like nanoparticles, nanofibers, and nanoparticles-embedded films, membranes, gels, and nanofibers.

Diabetic foot, leg ulcers and decubitus ulcers affect millions of individuals worldwide leading to poor quality of life, pain and in several cases to limb amputations. Despite the global dimension of this clinical problem, limited progress has been made in developing more efficacious wound dressings, the design of which currently focusses on wound protection and control of its exudate volume. The present in vitro study systematically analysed seven types of clinically-available wound dressings made of different biomaterial composition and engineering. Their physicochemical properties were analysed by infrared spectroscopy, swelling and evaporation tests and variable pressure scanning electron microscopy. These properties were linked to the interactions with inflammatory cells in simulated normoglycaemic and hyperglycaemic conditions. It was observed that the swelling behaviour and evaporation prevention at different glucose levels depended more on the engineering of the fibres than on the hydrophilicity and hydrophobicity of their biomaterials. Likewise, the data show that the engineering of the dressings as either non-woven or woven or knitted fibres seems to determine the swelling behaviour and interactions with inflammatory cells more than their polymer composition. Dressings presenting absorbent layers made of synthetic, non-woven fibres supported the adhesion of monocytes macrophages and stimulate the release of factors known to play a role in the chronic inflammation. Non-woven absorbent layers based on carboxymethyl cellulose mainly stimulating the iNOS, an enzyme producing free radicals; in the case of Kerracel this was combined with a swelling of fibres preventing the penetration of cells. Kaltostat, an alginate-based wound dressing, showed the higher level of swelling and supporte the adhesion of inflammatory cells with limited activation. Knitted dressings showed a limited adhesion of inflammatory cells. In conclusion, this work offers insights about the interactions of these wound dressings with inflammatory cells upon exudate changes thus providing further criteria of choice to clinicians.

Health and disease are intricately intertwined and often determined by the delicate balance of biological processes. Cytokines, a family of small signalling molecules, are pivotal in maintaining this balance, ensuring the body's immune system functions optimally. In a healthy condition, cytokines act as potent mediators of immune responses. They orchestrate the activities of immune cells, coordinating their proliferation, differentiation, and migration. This intricate role of cytokine signalling enables the body to effectively combat infections, repair damaged tissues, and regulate inflammation. However, the delicate equilibrium of cytokine production is susceptible to disruption. Excessive or abnormal cytokine levels can lead to a cascade of pathological conditions, including autoimmune diseases, chronic inflammation, infections, allergies, and even cancer. Interestingly, from the bunch of cytokines, few cytokines play an essential role in maintaining the balance between normal physiological status and diseases. In this review, we have appraised key cytokines' potential role and feedback loops in augmenting the imbalances in the body's biological functions, presenting a critical link between inflammation and disease pathology. Moreover, we have also highlighted the significance of cytokines and their molecular interplay, particularly in the recent viral pandemic COVID-19 disease. Hence, understandings regarding the interplay between viral infection and cytokine responses are essential and fascinating for developing effective therapeutic strategies.

Cathelicidins are a group of cationic, amphipathic peptides that play a vital role in the innate immune response of many vertebrates, including humans. Produced by immune and epithelial cells, they serve as natural defenses against a wide range of pathogens, including bacteria, viruses, and fungi. In humans, the cathelicidin LL-37 is essential for wound healing, maintaining skin barrier integrity, and combating infections. Cathelicidins of different origins have shown potential in treating various skin conditions, including melanoma, acne, and diabetic foot ulcers. Despite their promising therapeutic potential, cathelicidins face significant challenges in clinical application. Many peptide-based therapies have failed in clinical trials due to unclear efficacy and safety concerns. Additionally, the emergence of bacterial resistance, which contradicts initial claims of non-resistance, further complicates their development. To successfully translate cathelicidins into effective clinical treatments, therefore, several obstacles must be addressed, including a better understanding of their mechanisms of action, sustainable large-scale production, optimized formulations for drug delivery and stability, and strategies to overcome microbial resistance. This review examines the current knowledge of cathelicidins and their therapeutic applications and discusses the challenges that hinder their clinical use and must be overcome to fully exploit their potential in medicine.

The lack of the immune component in most of the engineered skin models remains a challenge to study the interplay between different immune and non-immune cell types of the skin. Immunocompetent humanin vitroskin models offer potential advantages in recapitulatingin vivolike behavior which can serve to accelerate translational research and therapeutics development for skin diseases. Here we describe a three-dimensional human full-thickness skin (FTS) equivalent incorporating polarized M1 and M2 macrophages from human peripheral CD14+monocytes. This macrophage-incorporated FTS model demonstrates discernible immune responses with physiologically relevant cytokine production and macrophage plasticity under homeostatic and lipopolysaccharide stimulation conditions. M2-incorporated FTS recapitulates skin fibrosis phenotypes with transforming growth factor-β1 treatment as reflected by significant collagen deposition and myofibroblast expression, demonstrating a M2 potentiation effect. In conclusion, we successfully biofabricated an immunocompetent FTS with functional macrophages in a high-throughput (HT) amenable format. This model is the first step towards a HT-assay platform to develop new therapeutics for skin diseases.

Konjac glucomannan (KGM) molecular chains contain a small amount of acetyl groups and a large number of hydroxyl groups, thereby exhibiting exceptional water retention and gel-forming properties. To meet diverse requirements, KGM undergoes modification processes such as oxidation, acetylation, grafting, and cationization, which reduce its viscosity, enhance its mechanical strength, and improve its water solubility. Researchers have found that KGM and its derivatives can regulate the polarization of macrophages, inducing their transformation into classically activated M1-type macrophages or alternatively activated M2-type macrophages, and even facilitating the interconversion between M1 and M2 phenotypes. Concurrently, the modulation of macrophage polarization states holds significant importance for chronic wound healing, inflammatory bowel disease (IBD), antitumor therapy, tissue engineering scaffolds, oral vaccines, pulmonary delivery, and probiotics. Therefore, KGM has the advantages of both immunomodulatory effects (biological activity) and gel-forming properties (physicochemical properties), giving it significant advantages in a variety of biomedical engineering applications.

Blood concentrates like platelet rich fibrin (PRF) have been established as a potential autologous source of cells and growth factors with regenerative properties in the field of dentistry and regenerative medicine. To further analyze the effect of PRF on bone tissue regeneration, this study investigated the influence of liquid PRF matrices on human healthy primary osteoblasts (pOB) and co-cultures composed of pOB and human dermal vascular endothelial cells (HDMEC) as in vitro model for bone tissue regeneration. Special attention was paid to the PRF mediated influence on osteoblastic differentiation and angiogenesis. Based on the low-speed centrifugation concept, cells were treated indirectly with PRF prepared with a low (44 g) and high relative centrifugal force (710 g) before the PRF mediated effect on osteoblast proliferation and differentiation was assessed via gene and protein expression analyses and immunofluorescence. The results revealed a PRF-mediated positive effect on osteogenic proliferation and differentiation accompanied by increased concentration of osteogenic growth factors and upregulated expression of osteogenic differentiation factors. Furthermore, it could be shown that PRF treatment resulted in an increased formation of angiogenic structures in a bone tissue mimic co-culture of endothelial cells and osteoblasts induced by the PRF mediated increased release of proangiogenic growth factors. The effects on osteogenic proliferation, differentiation and vascularization were more evident when low RCF PRF was applied to the cells. In conclusion, PRF possess proosteogenic, potentially osteoconductive as well as proangiogenic properties, making it a beneficial tool for bone tissue regeneration.

Wound healing is interaction of a complex cascade of cellular/biochemical actions leading to restoration of structural and functional integrity with regain of injured tissues strength. This study was aimed at evaluation of application of ethanolic extract of propolis-loaded poly(-lactic-co-glycolic acid) nanoparticles (EEP-PLGA NPs) on wound healing in diabetic rats. Sixty rats were randomized into four groups of 15 rats each: In control group (Control) diabetic wound was treated with normal saline. In Carrier 1 group diabetic wound was treated with PLGA nanoparticles based solution. In Carrier 2 group the diabetic wound was treated with EEP. In Treatment group animals received EEP-PLGA NPs on the wound. Wound size was measured on 7, 14 and 21 days after surgery. The expression of p53, bcl-2, Caspase III, were evaluated using reverse-transcription PCR and Immunohistochemical staining. The Treatment group had significantly reduced the wound size compared to other groups (P = 0.001). histological and morphometric studies, and mean rank of the qualitative studies demonstrated that there was significant difference between Treatment group and other groups (P < .05). Observations demonstrated that ethanolic extract of propolis-loaded PLGA nanoparticles significantly shortened the inflammatory phase and accelerated the cellular proliferation. Accordingly, the animals in Treatment group revealed significantly (P < .05) higher fibroblast distribution/one mm2 of wound area and rapid re epithelialization. The mRNA levels of bcl-2, p53 and caspase III were remarkably (P < .05) higher in Treatment group compared to control and animals. The immunohistochemical analyzes confirmed the RT-PCR findings. EEP-PLGA NPs offered potential advantages in wound healing acceleration and improvement through angiogenesis stimulation, fibroblast proliferation and granulation tissue formation in early days of healing phases, acceleration in diabetic wound repair associated with earlier wound contraction and stability of damaged area by rearrangement of granulation tissue and collagen fibers.

Hair is an intricate biological structure that originates from hair follicles (HFs), which are complex mini-organs embedded in the skin. Each HF undergoes continuous cycles of growth (anagen), regression (catagen), and rest (telogen), driven by intricate signaling pathways and interactions between epithelial and mesodermal cells. The development of HFs requires the interplay of several key signaling pathways, including Wnt, Shh, Notch, and BMP. The Wnt pathway is primarily involved in induction, Shh is essential for early organogenesis and later stages of cytodifferentiation, Notch signaling governs the fate of HF stem cells, and BMP plays a role in cytodifferentiation. Hair health is closely associated with psychological well-being and personal distress. While hair loss (alopecia) does not impact biological health, it significantly affects social well-being. Therefore, a deep understanding of the molecular mechanisms underlying HF development is crucial for developing treatments for hair-related problems and improving hair health. This knowledge has led to significant advancements in therapeutic applications, particularly in treating hair loss disorders, enhancing wound healing, and developing cosmetic treatments. This paper aims to review the molecular mechanisms involved in HF development, with an emphasis on their potential impact on human health and well-being.

Introduction: To accelerate cutaneous wound healing and prevent scarring, regenerative approaches such as injecting a mechanically derived tissue stromal vascular fraction (tSVF) are currently under clinical and laboratory investigations. The aim of our study was to investigate a platform to assess the interaction between skin-derived extracellular matrix (ECM) hydrogels and tSVF and their effects on their microenvironment in the first ten days of culture. Material and Methods: A tSVF mixed with ECM hydrogel was cultured for ten days. After 0, 3, 5, and 10 days of culture viability, histology, immunohistochemistry, gene expression, and collagen alignment and organization were assessed. Results: The viability analysis showed that tSVF remained viable during 10 days of culture and seemed to remain within their constitutive ECM. The fiber analysis demonstrated that collagen alignment and organization were not altered. No outgrowth of capillaries was observed in (immuno)histochemical staining. The gene expression analysis revealed that paracrine factors TGFB1 and VEGFA did not change and yet were constitutively expressed. Pro-inflammatory factors IL1B and IL6 were downregulated. Matrix remodeling gene MMP1 was upregulated from day three on, while MMP14 was upregulated at day three and ten. Interestingly, MMP14 was downregulated at day five compared to day three while MMP2 was downregulated after day zero. Conclusions: Skin-derived ECM hydrogels appear to be a versatile platform for investigating the function of a mechanically isolated adipose tissue stromal vascular fraction. In vitro tSVF remained viable for 10 days and sustained the expression of pro-regenerative factors, but is in need of additional triggers to induce vascularization or show signs of remodeling of the surrounding ECM. In the future, ECM-encapsulated tSVF may show promise for clinical administration to improve wound healing.

Biomaterials intended for intrabone implantation are extensively utilized in orthopedic and dental applications. Their surface properties, particularly hydrophilicity, significantly influence the biological interactions surrounding the implant, ultimately determining the implant's in vivo fate. Recently, the role of osteoimmunomodulation in these implantable biomaterials has been recognized for its importance in regulating biomaterial-mediated osteogenesis. Consequently, it is imperative to elucidate the correlation between hydrophilicity and the immune response for the development of osteoimmunomodulatory implants. Herein, this review highlights recent advances in osteoimmunomodulation of biomaterials after intrabone implantation from a novel perspective-surface hydrophilicity, and summarizes the series of immune reactions and subsequent bone remodeling that occur in response to hydrophilic implants, focusing on protein adsorption, the behaviors of major immune cells, and osteoimmunomodulation-enhanced angiogenesis and osteogenesis. Hydrophilic biomaterials have the capacity to alter the surrounding immune microenvironment and accelerate the process of material-tissue bonding, thereby facilitating the successful integration of biomaterials with tissue. Collectively, the authors hope that this article provides strategies for modulating hydrophilicity to achieve osteoimmunomodulatory performance and further promotes the development of novel implantable biomaterials for orthopedic and dental applications.

Chronic or non-healing wounds, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers (PUs) and wounds in the elderly etc., impose significant biological, social, and financial burdens on patients and their families. Despite ongoing efforts, effective treatments for these wounds remain elusive, costing the United States over US$25 billion annually. The wound healing process is notably slower in the elderly, partly due to cellular senescence, which plays a complex role in wound repair. High glucose levels, reactive oxygen species, and persistent inflammation are key factors that induce cellular senescence, contributing to chronic wound failure. This suggests that cellular senescence may not only drive age-related phenotypes and pathology but also be a key mediator of the decreased capacity for trauma repair. This review analyzes four aspects: characteristics of cellular senescence; cytotoxic stressors and related signaling pathways; the relationship between cellular senescence and typical chronic non-healing wounds; and current and future treatment strategies. In theory, anti-aging therapy may influence the process of chronic wound healing. However, the underlying molecular mechanism is not well understood. This review summarizes the relationship between cellular senescence and chronic wound healing to contribute to a better understanding of the mechanisms of chronic wound healing.

Chronic wounds present a significant healthcare challenge marked by complexities such as persistent bleeding, inhibited cell proliferation, dysregulated inflammation, vulnerability to infection, and compromised tissue remodeling. Conventional wound dressings often prove inadequate in addressing the intricate requirements of chronic wound healing, leading to slow healing and heightened susceptibility to infections in patients with prolonged medical conditions. Bacterial biofilms in chronic wounds pose an additional challenge due to drug resistance. Advanced wound dressings have emerged as promising tools in expediting the healing process. Among these, pH-responsive polysaccharide-based hydrogels exhibit immense prospect by adapting their functions to dynamic wound conditions. Despite their potential, the current literature lacks a thorough review of these wound dressings. This review bridges this gap by meticulously examining factors related to chronic wounds, current strategies for healing, and the mechanisms and potential applications of pH-responsive hydrogel wound dressings as an emerging therapeutic solution. Special focus is given to their remarkable antibacterial properties and significant self-healing abilities. It further explores the pH-monitoring functions of these dressings, elucidating the associated pH indicators. This synthesis of knowledge aims to guide future research and development in the field of pH-responsive wound dressings, providing valuable insights into their potential applications in wound care.

The poor healing characteristics of diabetic foot ulcers are partially attributed to diabetes-induced pro-inflammatory wounds. Our previous study reported that both miR-146a-5p and miR-200b-3p decrease endothelial inflammation in human aortic endothelial cells and db/db diabetic mice. Although miR-146a-5p has been reported to improve diabetic wound healing, the role of miR-200b-3p is not clear. This study compared the roles of these miRNAs in diabetic wound healing. Two 8-mm full-thickness wounds were created in 12-week-old male db/db mice on the left and right back. After surgery, 100 ng miR-146a-5p, miR-200b-3p, or miR-negative control (NC) was injected in each wound. Full-thickness skin samples were harvested from mice at the 14th day for real-time polymerase chain reaction and immunohistochemistry analyses. At the 14th day, the miR-200b-3p group showed better wound healing and greater granulation tissue thickness than the miR-146a-5p group. The miR-200b-3p group showed a significant decrease of IL-6 and IL-1β gene expression and a significant increase of Col3α1 gene expression compared to those in the miR-NC group. The miR-200b-3p group had the lowest gene expression of TGF-β1, followed by the miR-146a-5p and miR-NC groups. Our findings suggest that the miR-200b-3p group had better healing characteristics than the other two groups. Immunohistochemical staining revealed that CD68 immunoreactivity was significantly decreased in both the miR-146a-5p and miR-200b-3p groups compared with that in the miR-NC group. In addition, CD31 immunoreactivity was significantly higher in the miR-200b-3p group than in the miR-146a-5p group. In conclusion, these results suggest that miR-200b-3p is more effective than miR-146a-5p in promoting diabetic wound healing through its anti-inflammatory and pro-angiogenic effects.

Chronic wounds present a significant clinical challenge due to their prolonged healing time and susceptibility to infection. Boron, a trace element with diverse biological functions, has emerged as a promising therapeutic agent in wound healing. This review article comprehensively investigates the mechanisms underlying the beneficial effects of boron compounds in wound healing. Boron exerts its healing properties through multiple pathways, including anti-inflammatory, antimicrobial, antioxidant, and pro-proliferative effects. Inflammation is a crucial component of the wound-healing process, and boron has been shown to modulate inflammatory responses by inhibiting pro-inflammatory cytokines and promoting the resolution of inflammation. Furthermore, boron exhibits antimicrobial activity against a wide range of pathogens commonly associated with chronic wounds, thereby reducing the risk of infection and promoting wound closure. The antioxidant properties of boron help protect cells from oxidative stress, a common feature of chronic wounds that can impair healing. Additionally, boron stimulates cell proliferation and migration, as well as essential tissue regeneration and wound closure processes. Overall, this review highlights the potential of boron as a novel therapeutic approach for treating chronic wounds, offering insights into its diverse mechanisms of action and clinical implications.

Astragaloside IV (ASIV) promotes the proliferation of key cells, endothelial progenitor cells (EPCs), during the wound healing process, while exosomes and hydrogels are ideal drug delivery carriers. This study aims to explore the mechanism of action of the "ROS-responsive hydrogel-engineered EPCs-targeted exosomes" composite ASIV delivery system (PF-PEG@ASIV-EXO) in diabetic wound healing. Surface markers of EPCs and PF-PEG@ASIV-EXO were detected separately. The degradation rate of PF-PEG@ASIV-EXO was assessed after coculturing with human dermal fibroblasts (HDF), immortalized human epidermal cells (HaCAT), and human EPCs, and the biocompatibility of EPCs and PF-PEG@ASIV-EXO was evaluated through exosome release and uptake. The effects of PF-PEG@ASIV-EXO on the viability, angiogenesis, ferroptosis, and mitochondria of high-glucose-treated EPCs (HS-EPCs) were investigated. A diabetic wound rat model was established, and the effects of PF-PEG@ASIV-EXO on diabetic wounds were evaluated through HE and Masson staining, as well as levels of VWF, CD31, and ferroptosis in the skin. EPCs were successfully isolated, and PF-PEG@ASIV-EXO was successfully constructed. PF-PEG@ASIV-EXO exhibited a high degradation rate within EPCs, and both EPCs and PF-PEG@ASIV-EXO showed good biocompatibility. PF-PEG@ASIV-EXO promoted the vitality and angiogenesis of EPCs, inhibited ferroptosis, and mitigated mitochondrial damage. Following treatment with PF-PEG@ASIV-EXO, the healing of diabetic rat skin accelerated, accompanied by elevated expression of VWF and CD31, and reduced ferroptosis levels. PF-PEG@ASIV-EXO hydrogel inhibits ferroptosis, promotes angiogenesis, and thereby accelerates the healing of diabetic wounds.

Burn injuries are serious injuries that have a big impact on a person's health and can even cause death. Incurring severe burns can incite an immune response and inflammation within the body, alongside metabolic changes. It is of utmost importance to grasp the fact that the effects of the burn injury extend beyond the body, affecting the mind and overall well-being. Burn injuries cause long-lasting changes that need to be taken care of in order to improve their quality of life. The intricate process of skin regeneration at the site of a burn wound involves a complex and dynamic interplay among diverse cells, growth factors, nerves, and blood vessels. Exciting opportunities have arisen in the field of stem cells and regenerative medicine, allowing us to explore the development of cell-free-based alternatives that can aid in the treatment of burn injuries. These cell-free-based therapies have emerged as a promising facet within regenerative medicine. Exosomes, also referred to as naturally occurring nanoparticles, are small endosome-derived vesicles that facilitate the delivery of molecular cargo between the cells, thus allowing intercellular communication. The knowledge gained in this field has continued to support their therapeutic potential, particularly in the domains of wound healing and tissue regeneration. Notably, exosomes derived from mesenchymal stem cells (MSCs) can be safely administered in the system, which is then adeptly uptaken and internalized by fibroblasts/epithelial cells, subsequently accelerating essential processes such as migration, proliferation, and collagen synthesis. Furthermore, exosomes released by immune cells, specifically macrophages, possess the capability to modulate inflammation and effectively diminish it in adjacent cells. Exosomes also act as carriers when integrated with a scaffold, leading to scarless healing of cutaneous wounds. This comprehensive review examines the role of exosomes in burn wound healing and their potential utility in regeneration and repair.

The incidence of skin trauma is high and the repair process is complex, often leading to poor healing and other issues, which can result in significant economic and social burdens. Traditional Chinese medicine (TCM) is a valuable resource with proven effectiveness and safety in wound repair, widely utilized in clinical practice. A systematic analysis of wound healing with a focus on TCM research progress holds both academic and clinical importance.

This article reviews the research progress of TCM in promoting wound healing, and provides basic data for the development of innovative drugs that promote wound healing.

This article provides a review of the literature from the past decade and conducts a thorough analysis of various databases that contain reports on the use of TCM for wound repair. The data for this systematic research was gathered from electronic databases including CNKI, SciFinder, and PubMed. The study explores and summarizes the research findings and patterns by creating relevant charts.

This study reviewed the mechanism of wound healing, experimental TCM methods to promote wound healing, the theory and mode of action of TCM to promote wound healing, the active ingredients of TCM that promote wound healing, the efficacy of TCM formulae to promote wound healing, and the potential toxicity of TCM and its antidotes. This study enriched the theory of TCM in promoting wound healing.

Skin wound healing is a complex process that can be influenced by various internal and external factors. This article offers a theoretical foundation for exploring and utilizing TCM resources that enhance wound repair. By analyzing a range of TCM that promote wound healing, the article highlights the clinical importance and future potential of these medicines in promoting wound healing.

Delayed or stalled healing in open wounds can result from persisting chronic inflammation related to infection and/or persistent bacterial colonisation and biofilm. Treatment of hard-to-heal wounds focuses on debridement and exudate management, but also on infection prevention and control. Silver dressings have been evaluated in randomised clinical trials (RCTs); this meta-analysis evaluated the efficacy and safety of a silver ion-releasing foam dressing (Biatain Ag; Coloplast A/S, Denmark) to treat hard-to-heal wounds.

Literature databases (PubMed and Cochrane Library) were searched for studies on silver ion-releasing foam dressings in the treatment of hard-to-heal wounds. Individual patient data from four RCTs were obtained and included in the meta-analysis.

Findings showed that treatment with the silver ion-releasing foam dressing was associated with a significantly higher relative reduction in wound area after four (least squares-mean difference (LS-MD): -12.55%, 95% confidence interval (CI): (-15.95, -9.16); p<0.01) and six weeks of treatment (LS-MD: -11.94%, 95%CI: (-17.21, -6.68); p<0.01) compared with controls. Significant benefits were also observed for time to disappearance of odour (hazard ratio: 1.61, 95%CI: (1.31, 1.98); p<0.01), relative reduction of exudate (LS-MD: -5.15, 95%CI: (-7.36, -2.94); p<0.01), proportion of patients with periwound erythema (relative risk (RR): 0.81, 95%CI: (0.69; 0.94); p<0.01), and less pain at dressing removal (LS-MD: -0.35, 95%CI: (-0.63, -0.06); p=0.02). No differences regarding safety outcomes were identified.

This meta-analysis has demonstrated beneficial outcomes and a good tolerability profile for silver ion-releasing foam dressings in the treatment of moderate-to-highly exuding wounds with delayed healing compared with control dressings.

The (M2M + TGF-β)@HAMA hydrogel dressing improves the outcomes of dysregulated chronic wound healing by protecting the open wound from repeated bacterial infections, reprogramming endogenous monocytes and M1 macrophages into an M2-phenotype, as well as enhancing fibroblastic proliferation and migration for matrix remodeling and granulation tissue formation.Image 1.

Chronic non-healing wounds pose significant challenges due to an elevated inflammatory response caused in part by bacterial contamination (Physiol Rev. 2019;99:665). These wounds lead to billions being spent in the health care system worldwide (N Engl J Med. 2017;376:2367, Int J Pharm. 2014;463:119). We studied the in-vitro and in-vivo antimicrobial effects of a multimodal wound matrix (MWM) against two common wound pathogens, Methicillin-Resistant Staphylococcus aureus (MRSA USA300) and Pseudomonas aeruginosa ATCC 27312 (PA27312) (Int Wound J. 2019;16:634). The in-vitro study conducted was a zone of inhibition test with the two microbes at 104 Log CFU/mL inoculated on Tryptic soy agar with 5% sheep blood (TSAII) plates. Treatments used were MWM, Mupirocin (Positive control for MRSA), Silver Sulfadiazine (Positive Control for PA), Petrolatum and Sterile Saline (both serving as Negative Controls). Treatments were allowed to diffuse into the agar for 3 h and then were incubated for 24 h at 37°C. The in-vivo study utilized a deep dermal porcine wound model (22 × 22 × 3 mm) created on six animals. Three animals were inoculated with MRSA USA300 and the other three with PA27312 with each allowing a 72-h biofilm formation. After 72 h, baseline wounds were assessed for bacterial concentration and all remaining wounds were treated with either MWM alone, Silver Treatment or Untreated Control. Wounds were assessed on days 4, 8 and 12 after treatment application for microbiological analysis. In-vitro, MWM exhibited significant inhibition of MRSA USA300 and PA27312 growth when compared to negative controls (p ≤ 0.05). Likewise, in-vivo, the MWM-treated wounds exhibited a significant (p ≤ 0.05) bacterial reduction compared to all other treatment groups, especially on days 8 and 12 for both pathogens. MWM demonstrated promise in addressing colonized wounds with biofilms. Additional studies on MWM's benefits and comparisons with existing treatments are warranted to optimize wound care strategies (Adv Wound Care. 2021;10:281).

Wound healing is an orderly sequence of events restoring the integrity of the damaged tissue. It consists of inflammatory, proliferation, and remodeling phases. The objective of the current study was to investigate the effect of local transplantation of cultured macrophage loaded with mesenchymal stem cell/macrophage culture supernatants on wound healing. Sixty-four healthy adult male Wistar rats were randomized into 4 groups of sixteen animals each: 1) SHAM group. 2) MAC-MSC/SN group: One-milliliter application of a mixture comprising mesenchymal stem cell and macrophage culture supernatants in a 1:1 ratio was administered locally to the wound bed. 3) MAC group: Local transplantation of macrophage cells cultured in the wound bed. 4) MAC + MAC-MSC/SN group: Local transplantation of cultured macrophage in combination with mesenchymal stem cell/ macrophage culture supernatants in the wound bed. An incisional wound model was used for biomechanical studies, while an excisional wound model was used for biochemical, histopathological, and planimetric assessments. The wound area was significantly reduced in the MAC + MAC-MSC/SN group compared to other groups (P < 0.05). Biomechanical measurements from the MAC + MAC-MSC/SN group were significantly higher compared to other experimental groups (P < 0.05). Biochemical and quantitative histopathological analyses revealed a significant difference between MAC + MAC-MSC/SN and other groups (P < 0.05). MAC + MAC-MSC/SN showed the potential to improve wound healing significantly. This appears to work by angiogenesis stimulation, fibroblast proliferation, inflammation reduction, and granulation tissue formation during the initial stages of the healing process. This accelerated healing leads to earlier wound area reduction and enhanced tensile strength of the damaged area due to the reorganization of granulation tissue and collagen fibers.

Wound healing is a critical process in tissue repair following injury, and traditional herbal therapies have long been utilized to facilitate this process. This review delves into the mechanistic understanding of the significant contribution of pharmacologically demonstrated natural products in wound healing. Natural products, often perceived as complex yet safely consumed compared to synthetic chemicals, play a crucial role in enhancing the wound-healing process. Drawing upon a comprehensive search strategy utilizing databases such as PubMed, Scopus, Web of Science, and Google Scholar, this review synthesizes evidence on the role of natural products in wound healing. While the exact pharmacological mechanisms of secondary metabolites in wound healing remain to be fully elucidated, compounds from alkaloids, phenols, terpenes, and other sources are explored here to delineate their specific roles in wound repair. Each phytochemical group exerts distinct actions in tissue repair, with some displaying multifaceted roles in various pathways, potentially enhancing their therapeutic value, supported by reported safety profiles. Additionally, these compounds exhibit promise in the prevention of keloids and scars. Their potential alongside economic feasibility may propel them towards pharmaceutical product development. Several isolated compounds, including chlorogenic acid, thymol, and eugenol from natural sources, are undergoing investigation in clinical trials, with many reaching advanced stages. This review provides mechanistic insights into the significant role of pharmacologically demonstrated natural products in wound healing processes.

Wound healing is a complex process influenced by a variety of environmental factors. Dressing materials play a critical role in creating barriers against contaminants, maintaining optimal moisture levels, and absorbing wound exudate. Therefore, selecting materials tailored to wound characteristics is crucial for enhancing outcomes. Hyaluronic acid (HA) is a natural biocompatible polymer that supports healing by regulating inflammation and promoting tissue repair. This study compared HA- and hydrocolloid-based hydrogels in a rat model to optimize wound care strategies.

Full-thickness dermal wounds (diameter, 8 mm) were created on the dorsal skin of 12 Sprague-Dawley rats under sevoflurane anesthesia. The wounds were treated with HA/silver sulfadiazine gel (group A), hydrocolloid gel (group B), or left untreated (control), all covered with a transparent dressing. Biopsy specimens on days 3, 7, and 21 were used to assess histological parameters: inflammatory cell infiltration, fibroblast infiltration, collagen deposition, neovascularization, and epithelial thickness, using a semi-quantitative scoring system. Histological analyses were conducted blindly, and statistical analyses were performed using the Kruskal-Wallis test (p< 0.05).

On day 3, group A showed significantly higher inflammatory cell infiltration and collagen deposition than other groups, indicating extracellular matrix formation. By day 7, angiogenesis was highest in group A, followed by group B and controls. By day 21, all wounds had completely healed. Epithelial layer thickness, reflecting inflammation and fibroblast maturity, was significantly higher in group A.

This study compared HA-based hydrogel and hydrocolloid-based dressings through histological analyses to elucidate wound healing mechanics. HA-based hydrogel dressings significantly enhanced wound recovery. However, generalizing these outcomes requires future studies to expand the range of effective wound treatment materials. These findings underscore the potential of HA-based dressings to enhance clinical outcomes in wound management, suggesting avenues for improving therapeutic strategies.

The design and development of wound-dressing hydrogels with desirable therapeutic effects and proper mechanical and self-healing properties are crucial in the healthcare sector. This research aims to prepare a new self-healing hydrogel based on Tragacanth, polyvinyl alcohol, and borax to be used as a wound dressing, the hydrogel was first prepared through a simple and one-pot reaction. The efficiency of the resulting product was then assessed based on the rheological and self-healing tests as well as cellular tests on a mouse fibroblast cell line (L929) including toxicity and scratch tests as well as the investigation of the expression of TGFβ1, TGFβ2, and VEGF-A gens (using Real-time PCR). The synthesized hydrogel exhibited proper mechanical strength, high self-healing features, and no toxicity (cell viability >100 %). Rheological studies indicate that hydrogels with a higher borax content (PVA: B ratio of 5:1) exhibit a higher storage modulus across all frequencies. The presence of hydrogel improved the migration of the L929 cells and scratch healing. The hydrogel also caused a significant improvement in the expression of the growth factors of the genes (P < 0.001). Therefore, it can be concluded that the prepared wound dressing can actively contribute to wound healing, opening promising potentials in medical applications.

Chronic wounds pose a significant challenge to healthcare. Stemming from impaired wound healing, the consequences can be severe, ranging from amputation to mortality. This comprehensive review explores the multifaceted impact of chronic wounds in medicine and the roles that diet and nutritional pathologies play in the wound-healing process. It has been well established that an adequate diet is crucial to proper wound healing. Nutrients such as vitamin D, zinc, and amino acids play significant roles in cellular regeneration, immune functioning, and collagen synthesis and processing. Additionally, this review discusses how patients with chronic conditions like diabetes, obesity, and nutritional deficiencies result in the formation of chronic wounds. By integrating current research findings, this review highlights the significant impact of the genetic make-up of an individual on the risk of developing chronic wounds and the necessity for adequate personalized dietary interventions. Addressing the nutritional needs of individuals, especially those with chronic conditions, is essential for improving wound outcomes and overall patient care. With new developments in the field of genomics, there are unprecedented opportunities to develop targeted interventions that can precisely address the unique metabolic needs of individuals suffering from chronic wounds, thereby enhancing treatment effectiveness and patient outcomes.

Dendritic cells (DCs) are antigen-presenting cells that reside in peripheral tissues and are responsible for initiating adaptive immune responses. As gatekeepers of the immune system, DCs need to continuously explore their surroundings, for which they can rapidly move through various types of connective tissue and basement membranes. DC motility has been extensively studied on flat 2D surfaces, yet the influences of a contextual 3D fibrous environment still need to be described. Using ECM-mimicking suspended fiber networks, we show how immature DCs (iDCs) engage in migratory cycles that allow them to transition from persistent migration to slow migratory states. For a subset of iDCs with high migratory potential, we report the organization of protrusions at the front of the cell body, which reverses upon treatment with inflammation agent PGE2. We identify an unusual migratory response to aligned fiber networks, whereby iDCs use filamentous protrusions to attach laterally and exert forces on fibers to migrate independent of fiber alignment. Increasing the fiber diameter from 200 to 500 nm does not significantly affect the migratory response; however, iDCs respond by forming denser actin bundles around larger diameters. Overall, the correlation between force-coupling and random migration of iDCs in aligned fibrous topography offers new insights into how iDCs might move in fibrous environments in vivo.

Skin wound healing is a well-coordinated process in which various cells and factors participate, during which fibroblast exhibits a critical role by exerting its multiple activities, including proliferation, migration, invasion, and differentiation. Previous studies have identified that fibromodulin (FMOD) could enhance dermal wound healing by promoting skin fibroblast activities, but little is known about its upstream regulator. We occasionally found that FMOD expression was downregulated in skin fibroblast by transforming growth factor-β1 treatment. It was hypothesized that microRNAs (miRNA) in skin fibroblast could downregulate FMOD production and blocking them would increase FMOD expression, as well as promote skin wound healing. Here, by utilizing combined analysis of miRNA microarray from the Gene Expression Omnibus database and miRNA targets prediction, we successfully identified a miRNA, termed miR-494-3p, could regulate FMOD production in human skin fibroblast (BJ fibroblast). The functional analysis revealed that miR-494-3p mimics could inhibit BJ fibroblast migration and invasion but not proliferation and differentiation, while miR-494-3p inhibition markedly promotes migration, invasion, and differentiation of BJ fibroblast. Moreover, we established FMOD overexpression (OE) and knockout BJ fibroblast. We found that FMOD OE could rescue the inhibitory effects of miR-494-3p mimics on the migration and invasion of BJ fibroblast. In contrast, the miR-494-3p inhibitor transfection could not enhance migration, invasion, and differentiation of FMOD KO BJ fibroblast. Together, our results suggest that miR-494-3p may be a potential target for skin wound management via regulating FMOD production.

Myocardial infarction (MI) is a common type of cardiovascular disease. The incidence of ventricular remodeling dysplasia and heart failure increases significantly after MI. The objective of this study is to investigate whether erythropoietin hepatocellular receptor B2 (EPHB2) can regulate myocardial injury after MI and explore its regulatory pathways. EPHB2 is significantly overexpressed in the heart tissues of MI mice. The downregulation of EPHB2 alleviates the cardiac function damage after MI. Knockdown EPHB2 alleviates MI-induced myocardial tissue inflammation and apoptosis, and myocardial fibrosis in mice. EPHB2 knockdown significantly inhibits the activation of mitogen activated kinase-like protein (MAPK) pathway in MI mice. Moreover, EPHB2 overexpression significantly promotes the phosphorylation of MAPK pathway-related protein, which can be reversed by MAPK-IN-1 (an MAPK inhibitor) treatment. In conclusion, silencing EPHB2 can mitigate MI-induced myocardial injury by inhibiting MAPK signaling in mice, suggesting that targeting EPHB2 can be a promising therapeutic target for MI-induced myocardial injury.

The biomedical application of self-healing materials in wet or (under)water environments is quite challenging because the insulation and dissociation effects of water molecules significantly reduce the reconstruction of material-interface interactions. Rapid closure with uniform tension of high-tension wounds is often difficult, leading to further deterioration and scarring. Herein, a new type of thermosetting water-resistant self-healing bioelastomer (WRSHE) was designed by synergistically incorporating a stable polyglycerol sebacate (PGS) covalent crosslinking network and triple hybrid dynamic networks consisting of reversible disulfide metathesis (SS), and dimethylglyoxime urethane (Dou) and hydrogen bonds. And a resveratrol-loaded WRSHE (Res@WRSHE) was developed by a swelling, absorption, and crosslinked network locking strategy. WRSHEs exhibited skin-like mechanical properties in terms of nonlinear modulus behavior, biomimetic softness, high stretchability, and good elasticity, and they also achieved ultrafast and highly efficient self-healing in various liquid environments. For wound-healing applications of high-tension full-thickness skin defects, the convenient surface assembly by self-healing of WRSHEs provides uniform contraction stress to facilitate tight closure. Moreover, Res@WRSHEs gradually release resveratrol, which helps inflammatory response reduction, promotes blood vessel regeneration, and accelerates wound repair.

Bioelectronics is a hot research topic, yet an important tool, as it facilitates the creation of advanced medical devices that interact with biological systems to effectively diagnose, monitor and treat a broad spectrum of health conditions. Electrical stimulation (ES) is a pivotal technique in bioelectronics, offering a precise, non-pharmacological means to modulate and control biological processes across molecular, cellular, tissue, and organ levels. This method holds the potential to restore or enhance physiological functions compromised by diseases or injuries by integrating sophisticated electrical signals, device interfaces, and designs tailored to specific biological mechanisms. This review explains the mechanisms by which ES influences cellular behaviors, introduces the essential stimulation principles, discusses the performance requirements for optimal ES systems, and highlights the representative applications. From this review, we can realize the potential of ES based bioelectronics in therapy, regenerative medicine and rehabilitation engineering technologies, ranging from tissue engineering to neurological technologies, and the modulation of cardiovascular and cognitive functions. This review underscores the versatility of ES in various biomedical contexts and emphasizes the need to adapt to complex biological and clinical landscapes it addresses.

Immune cell-mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+ T cells in normal or diabetic wound repair; however, the imbalance of CD4+ Th17/Tregs has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase Mixed-lineage-leukemia-1 (MLL1) directly regulates the Th17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Furthermore, we found that Notch receptor signaling regulates CD4+ Th cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+ T cells resulted in the loss of CD4+ Th cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling was upregulated in wound CD4+ Th cells, driving CD4+ T cells toward the Th17 cell phenotype. Treatment of diabetic wound CD4+ T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+ Th17 cells and IL-17A. This is the first study to our knowledge to identify the MLL1-mediated mechanisms responsible for regulating the Th17/Treg balance in normal and diabetic wounds and to define the complex role of Notch signaling in CD4+ T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+ Th cells may decrease pathologic inflammation through regulation of CD4+ T cell differentiation.