Wound healing is a complex and regulated process that involves the coordinated action of key signaling pathways. Activating transcription factor 3 (ATF3) is a stress-inducible protein that has recently emerged as a critical modulator of cellular responses to injury, including those involved in wound healing.

The aim of this study was to explore the repurposing of existing pharmacological agents to activate ATF3 and evaluate their potential to enhance wound healing factors.

We selected three compounds: retin-A, furosemide, and acrivastine based on their ability to modulate ATF3 expression and assessed their effects on wound healing processes in primary cell cultures. We evaluated wound healing-related genes such as LL-37, HBD-2, HBD-3, and VEGFA by qPCR, and a wound healing scratch assay using keratinocytes was conducted to evaluate cell migration.

Interestingly, retin-A induced the expression of key wound healing-related genes, including HBD-2, HBD-3, LL-37, and VEGF. Also, retin-A was the only compound showing wound healing effects, while furosemide and acrivastine did not exhibit any noticeable activity.

Our research highlights the potential of retin-A as therapeutic agents to improve wound healing, particularly in chronic wound models.

To review recent advances in the application of hair transplantation in wound healing and scar repair in special areas.

An extensive review of the literature on the application of hair transplantation in wound healing and scar repair in special areas was conducted, focusing on cellular functions, molecular mechanisms, and clinical applications.

Hair transplantation has been shown to effectively promote wound healing and scar repair in special areas. The underlying mechanisms are complex, but current understanding emphasizes a strong association with hair follicle-associated stem cells (including epidermal stem cells, dermal papilla cells, dermal sheath cells, etc).

The application of hair transplantation in wound healing and scar repair in special areas remains in its early stages. Further investigation into its mechanisms of action is essential, and randomized controlled trials are needed to establish its efficacy.

Diabetic foot ulcers (DFU) represent one of the most common side effects of diabetes, significantly impacting patients' quality of life and imposing considerable financial burdens on families and society at large. Despite advancements in therapies targeting lower limb revascularization and various medications and dressings, outcomes for patients with severe lesions remain limited. A recent breakthrough in DFU treatment stems from the development of mesenchymal stem cells (MSCs). MSCs have shown promising results in treating various diseases and skin wounds due to their ability for multidirectional differentiation and immunomodulation. Recent studies highlight that MSCs primarily repair tissue through their paracrine activities, with exosomes playing a crucial role as the main biologically active components. These exosomes transport proteins, mRNA, DNA, and other substances, facilitating DFU treatment through immunomodulation, antioxidant effects, angiogenesis promotion, endothelial cell migration and proliferation, and collagen remodeling. Mesenchymal stem cell-derived exosomes (MSC-Exo) not only deliver comparable therapeutic effects to MSCs but also mitigate adverse reactions like immune rejection associated with MSCs transplantation. This article provides an overview of DFU pathophysiology and explores the mechanisms and research progress of MSC-Exo in DFU therapy.

Articular cartilage defects, as a core pathologic feature in the progression of osteoarthritis, and their irreversible degenerative changes lead to functional impairment and socioeconomic burden for tens of millions of patients worldwide. Hydrogels have become key biomaterials in cartilage regeneration with the three-dimensional network structure, programmable mechanical properties, and cell-adaptive microenvironment of biomimetic extracellular matrix. In recent years, several hydrogel systems with in vitro/in vivo repair potential have been developed by modulating the material topology, dynamic mechanical response, and delivery of bioactive factors, and some of them have entered the clinical translation stage. This review systematically explains the biomimetic design principles of hydrogels. It analyzes the immunomodulation and chondrogenic mechanisms mediated by hydrogels, providing a theoretical framework for the development of next-generation smart cartilage repair materials.

The current research emphasis is on the development of wound dressings that can inhibit bacterial infections and facilitate the treatment of complex wound healing processes. In this study, nanofibrous mats of polyvinyl alcohol/chitosan/ZIF-67(PVA/Cs/ZIF-67) were prepared using an electrospinning technique, to investigate their antibacterial and regenerative properties in a rat model of full-thickness skin wounds. ZIF-67 nanoparticles, with an average size of approximately 373.5 nm and a high specific surface area of 1849 m2 g-1, were synthesized. The structural characteristics of the mats were analyzed using FTIR and FESEM. TEM and EDS analysis confirmed the presence of ZIF-67 crystals on the surface of the scaffolds. The PVA/Cs/ZIF-67 nanofibrous mat exhibits the requisite porosity, swelling ratio, WVTR, contact angle, and satisfactory mechanical properties in both dry and wet conditions. The cytotoxicity test demonstrated that the nanofibers containing ZIF-67 nanoparticles are biocompatible and capable of supporting cell adhesion. Moreover, the nanofibers exhibit notable antibacterial activity up to 90 %. Additionally, in animal studies, the PVA/Cs/ZIF-67 nanofibrous mat demonstrated superior efficacy in wound healing, accompanied by reduced inflammation and enhanced skin remodeling. This substantiates the considerable potential of the PVA/Cs/ZIF-67 nanofibrous mat as a wound dressing for full-thickness skin wound healing.

The challenge of ineffective wound healing, leading to chronic conditions necessitates the development of novel therapeutics strategies. Currently, a plethora of ailments have been researched and marketed globally to accelerate angiogenesis, re-epithelization, collagen synthesis, and proliferation. However, clinical translation remains challenging and requires rigorous pre- and post-clinical screening. Here, we have developed a formulation encapsulating Raloxifene, a repurposed drug, aimed to induce accelerated wound healing. Four different formulations (Forms 1, 2, 3, and 4) incorporating alginate, poloxamer 407 (P407), LiCl, and fetal bovine serum were prepared. Formulations were characterized by scanning electron microscopy, Fourier Transformation infrared spectroscopy, and rheology. In vitro assessments encompassing cell viability, cell migration, and drug release profile were conducted, subsequently, the in vivo wound healing potential was evaluated in Sprague Dawley (SD) rats. In results, we observed significant (p-value<0.05) wound healing by Form 3 at  14th due to up-regulation of TGFꞵ, Col-I and GSK3β genes. The histology results showed complete development of epidermis, endoderm and collagen fibers by Form 3, leading to complete healing. This formulation shows promise for clinical application in accelerated wound healing processes.

Ischemic wounds pose a challenge to conventional treatments due to insufficient blood and oxygen supply, exacerbating patient distress and often rendering traditional treatments ineffective. Thus, improving the healing rate of ischemic wounds remains a significant challenge requiring further research and solutions.

HaCaT and HUVEC were exposed to Sal-B under hypoxic conditions in vitro to assess proliferation, migration, and angiogenesis. Further, the mechanisms of action were investigated. In vivo, a mouse ischemic wound model was treated with Sal-B topically, with group comparisons including control (PBS), VEGF (100 ng/ml), and Sal-B (50 μmol/L, 100 μmol/L) utilizing immunofluorescence and H&E staining.

Salvianolic acid B notably increased HaCaT and HUVEC proliferation, migration, and tube formation in vitro and improved ischemic wound healing rates in vivo. It modulated crucial factors such as HIF-1α, TGF-β, MMP2, and bFGF.

This study indicates that salvianolic acid B promotes the healing of ischemic wounds under hypoxic conditions through multiple mechanisms. Specifically, salvianolic acid B effectively reduces the expression of HIF-1α while increasing the levels of TGF-β and bFGF, which are crucial for cell proliferation and new blood vessel formation during the wound healing process. Additionally, salvianolic acid B significantly enhances the proliferation, migration, and tube formation of HaCaT and HUVEC, accelerating wound closure, validating its potential for clinical application and highlighting new treatment strategies.

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Stroke is characterized with high morbidity, mortality and disability all over the world, and one of its core pathologies is blood-brain barrier (BBB) dysfunction. BBB plays a crucial physiological role in protecting brain tissues and maintaining homeostasis in central nervous system (CNS). BBB dysfunction serves as a key factor in the development of cerebral edema, inflammation, and further neurological damage in stroke patients. Currently, stem cells and their derived exosomes have shown remarkable potential in repairing the damaged BBB and improving neurological function after stroke. Stem cells repair the integrity of BBB through anti-inflammatory, antioxidant, angiogenesis and regulation of intercellular signaling mechanisms, while stem cell-derived exosomes, as natural nanocarriers, further enhance the therapeutic effect by carrying active substances such as proteins, RNAs and miRNAs. This review will present the latest research advances in stem cells and their exosomes in stroke treatment, as well as the challenges of cell source, transplantation timing, dosage, and route of administration in clinical application, aiming to discuss their mechanisms of repairing BBB integrity and potential for clinical application, and proposes future research directions. Stem cells and exosomes are expected to provide new strategies for early diagnosis and precise treatment of stroke, and promote breakthroughs in the field of stroke.

To investigate the effects of recombinant human type XVII collagen (RHCXVII) on the proliferation and adhesion of primary human keratinocytes (HPKCs) and to observe its clinical efficacy and safety in bullous pemphigoid (BP).

The RHCXVII was produced by genetic recombination technology and characterized by Fourier transform infrared (FTIR) spectroscopy. HPKCs were obtained from human foreskin and seeded onto culture plates coated with RHCXVII at concentrations of 10, 50 and 100μg/ml. The proliferation and relative adhesion of HPKCs were assessed by Cell Counting Kit-8 (CCK-8) and adhesion assays, respectively. Trajectories and velocities of HPKCs were recorded using a living cell imaging platform. To assess the effects of RHCXVII on HPKCs, E-cadherin, integrinα6 and laminin α3 mRNA levels were measured using reverse transcription-polymerase chain reaction (RT-PCR) assays. The patient test sites were treated with RHCXVII, while the contralateral sides served as controls. This was performed in combination with systemic glucocorticoid treatment. Bilateral wound healing was recorded at various time points and the efficacy in BP was assessed.

RHCXVII exhibited the anticipated structural characteristics of recombinant collagen and was deemed suitable for utilization in the present study. HPKCs demonstrated robust growth in culture plates precoated with RHCXVII, expressing keratin 15 (K15). After 3, 5 and 7 days, RHCXVII at a concentration of 10 µg/ml significantly promoted the proliferation of HPKCs (P<0.05). Furthermore, the optimal relative adhesion of HPKCs was observed when cells were cultured on RHCXVII at a concentration of 100 µg/ml (P<0.01). The mRNA levels of E-cadherin, integrinα6 and lamininα3 in HPKCs cultivated in wells coated with RHCXVII were considerably higher compared to the control group (P<0.05). The study encompassed a total of 12 patients. The mean time to resolution of lesions on the treated sides was 11.08 days, significantly shorter than the 13.42 days observed on the control sides. The mean time to blister resolution was 2.3 days shorter on the treated sides than on the controls. By day 7, the percentage improvement in wound healing compared to the baseline was 7.75 % greater on the treated sides than on the control sides. The study noted a high level of patient satisfaction and no occurrence of significant adverse events.

RHCXVII has the capacity to promote HPKC growth and adherence. In clinical applications, it has been demonstrated to accelerate wound healing in patients with bullous diseases (BD), thereby reducing the risk of subsequent secondary infection. Its potential as an adjunct treatment for wound repair in diseases such as BD merits further investigation.

Wound healing is one of the fundamental problems faced by the medical profession. Thus, there is a need for the development of biomaterials that are safe, economically viable, possess anti-inflammatory and antibacterial characteristics, and enhance wound healing. In this study, we designed a nanomicelle of Bletilla striata polysaccharide (BSP) self-loaded with Azithromycin (AZI). The properties are improved by physically blending Carbomer 940 (CBM) with Gelatin (GEL) to serve as the hydrogel matrix. The preparation was made by combining the nanomicelle, used as the precursor solution, with the gel matrix. It was designed to treat wound infections and promote healing. Relevant experiments indicate its excellent biocompatibility. The hydrogel not only promotes cell migration, proliferation, angiogenesis, and collagen deposition associated with skin healing, but also regulates the polarization of macrophages from the M1 to M2 phenotype, as well as the expression of related factors. Additionally, in vitro experiments demonstrate its good antibacterial activity. In addition, we demonstrated the gel's anti-inflammatory, antibacterial, and pro-healing effects in acute wounds and methicillin-resistant Staphylococcus aureus (MRSA) wounds. Therefore, the nanomicellar gel enhances antibacterial activity and related immune regulation, offering a new direction in the treatment of acute and chronic wounds.

Previous studies reported that esculin could protect against renal ischemia-reperfusion injury and liver injury, but its mechanism of action in skin wound healing is unclear. The Wnt/β-catenin signaling pathway plays a positive role in the wound healing process. This study aimed to investigate the effects of esculin on the rate and quality of skin wound healing in mice and explore its regulatory role in the Wnt/b-catenin signaling pathway.

Circular full-thickness skin wounds with a diameter of 8 mm were created on the backs of C57BL/6 mice, which were administered with 20 and 40 mg•kg-1 esculin through gastric lavage. Wound healing was monitored, and samples collected on day 14 were analyzed through hematoxylin-eosin and Masson staining to assess granulation tissue formation and collagen deposition. Immunohistochemistry, immunofluorescence, and Western blot evaluated markers of collagen synthesis, proliferation, angiogenesis, and proteins in the Wnt/b-catenin signaling pathway. National institutes of health/3T3 cells treated with esculin (50 and 200 μM) were analyzed for proliferating cell nuclear antigen (PCNA) expression to assess proliferative activity.

Compared with the model group, the esculin-treated groups exhibited significantly enhanced wound healing (P < 0.05), increased skin epithelial thickness (P < 0.01), and promoted extracellular matrix formation in mice. In addition, esculin significantly raised type I collagen alpha-1 chain and type III collagen alpha-1 chain protein levels (P < 0.05), boosted the expression of the cell proliferation marker PCNA and the vascular marker cluster of differentiation 31 in the dermis (P < 0.05), and upregulated proteins related to the Wnt/b-catenin signaling pathway and increased glycogen synthase kinase 3 beta phosphorylation in skin wound and NIH/3T3 cells (P < 0.05).

Esculin could upregulate and activate the Wnt/b-catenin signaling pathway to promote wound healing.

Artificial cells have emerged as synthetic entities designed to mimic the functionalities of natural cells, but their interactive ability with mammalian cells remains challenging. Herein, we develop a generalizable and modular strategy to engineer DNA-empowered stimulable artificial cells designated to regulate mammalian cells (STARM) via synthetic contact-dependent communication. Constructed through temperature-controlled DNA self-assembly involving liquid-liquid phase separation (LLPS), STARMs feature organized all-DNA cytoplasm-mimic and membrane-mimic compartments. These compartments can integrate functional nucleic acid (FNA) modules and light-responsive gold nanorods (AuNRs) to establish a programmable sense-and-respond mechanism to specific stimuli, such as light or ions, orchestrating diverse biological functions, including tissue formation and cellular signaling. By combining two designer STARMs into a dual-channel system, we achieve orthogonally regulated cellular signaling in multicellular communities. Ultimately, the in vivo therapeutic efficacy of STARM in light-guided muscle regeneration in living animals demonstrates the promising potential of smart artificial cells in regenerative medicine.

Diabetic foot ulcer (DFU) is one of the most common and complex complications of diabetes, but the underlying pathophysiology remains unclear. Single-cell RNA sequencing (scRNA-seq) has been conducted to explore novel cell types or molecular profiles of DFU from various perspectives. This study aimed to comprehensively analyze the potential mechanisms underlying impaired re-epithelization of DFU in a single-cell perspective.

We conducted scRNA-seq on tissues from human normal skin, acute wound, and DFU to investigate the potential mechanisms underlying impaired epidermal differentiation and the pathological microenvironment. Pseudo-time and lineage inference analyses revealed the distinct states and transition trajectories of epidermal cells under different conditions. Transcription factor analysis revealed the potential regulatory mechanism of key subtypes of keratinocytes. Cell-cell interaction analysis revealed the regulatory network between the proinflammatory microenvironment and epidermal cells. Laser-capture microscopy coupled with RNA sequencing (LCM-seq) and multiplex immunohistochemistry were used to validate the expression and location of key subtypes of keratinocytes.

Our research provided a comprehensive map of the phenotypic and dynamic changes that occur during epidermal differentiation, alongside the corresponding regulatory networks in DFU. Importantly, we identified two subtypes of keratinocytes: basal cells (BC-2) and diabetes-associated keratinocytes (DAK) that might play crucial roles in the impairment of epidermal homeostasis. BC-2 and DAK showed a marked increase in DFU, with an inactive state and insufficient motivation for epidermal differentiation. BC-2 was involved in the cellular response and apoptosis processes, with high expression of TXNIP, IFITM1, and IL1R2. Additionally, the pro-differentiation transcription factors were downregulated in BC-2 in DFU, indicating that the differentiation process might be inhibited in BC-2 in DFU. DAK was associated with cellular glucose homeostasis. Furthermore, increased CCL2 + CXCL2+ fibroblasts, VWA1+ vascular endothelial cells, and GZMA+CD8+ T cells were detected in DFU. These changes in the wound microenvironment could regulate the fate of epidermal cells through the TNFSF12-TNFRSF12A, IFNG-IFNGR1/2, and IL-1B-IL1R2 pathways, which might result in persistent inflammation and impaired epidermal differentiation in DFU.

Our findings offer novel insights into the pathophysiology of DFU and present potential therapeutic targets that could improve wound care and treatment outcomes for DFU patients.

Wound healing is crucial for restoring homeostasis in living organisms. Although wound response mechanisms have been studied extensively, the gene regulatory programs involved remain to be elucidated. Here, we used single-cell RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) analysis to profile the regulatory landscape of mouse corneal epithelium in early wound response.

We used our previously published single-cell data sets of homeostatic adult mouse corneal epithelium as the unwounded group. The wounded group data sets were obtained by sequencing the epithelium after an annular epithelial wound. Following the integration of the relevant data sets, the Seurat and ArchR packages were employed for single-cell RNA-seq and single-cell ATAC-seq data processing and downstream analysis, respectively. The Monocle 2 was used for pseudo-time analysis, CellChat for intercellular communication analysis, and pySCENIC for analyzing transcription factors. The expression of key genes was validated via immunofluorescence staining and quantitative real-time PCR.

Our data show that the number of cell type-specific genes decreases and the number of common transcriptional responses increases in early wound response. Concurrently, we find that the chromatin accessibility landscape undergoes significant changes across all epithelial cell types and that the wound-induced open regions are similarly distributed across the genome. Motif enrichment analysis shows that Fosl1/AP-1 binding site is highly enriched among the opened regions. However, by assessing the correlation between changes in chromatin accessibility and gene expression, we observe that only a small subset of wound-induced genes shows a high correlation with the accessibility of nearby chromatin.

Our study provides a detailed single-cell landscape for transcriptomic and epigenetic changes in mouse corneal epithelium during early wound response, which improved our understanding of the mechanisms of wound healing.

Diabetic foot ulcer (DFU) is a common complication of chronic diabetes mellitus. Oxygen plays a critical role in the healing process of DFU wounds by promoting cell migration and neovascularization. However, clinical hyperbaric oxygen (HBO) therapy predominantly uses systemic oxygen administration, posing challenges in inadequate DFU local oxygen penetration and potential ectopic organs oxygen toxicity. To address these challenges, a strategy to encapsulate oxygen with lipid microbubbles (OMBs) and incorporate them into a body temperature-sensitive heparin-pluronic copolymer hydrogel (HP/OMBs) have been developed. HP/OMBs showed high biocompatibility both in vitro and in vivo. After in situ administration, oxygen can be released from HP/OMBs to the local deep site of the DFU wounds under ultrasound (US) triggering. Thus, given its biocompatibility and practicality, the combined action of HP/OMBs and the US has important translational value in accelerating diabetic chronic wound healing.

Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.

Wound healing is a highly orchestrated process involving diverse cells and molecular interplays. Although wound healing assays are commonly used in the field of tissue repair, these experiments exhibit high variability due to their multifactorial nature, with many design factors remaining understudied. Here we report that precise localization of the wound site as well as the housing conditions have a pivotal role in dictating the healing dynamics in mice. We explore these key factors and highlight overlooked aspects of the repair process.

Diabetic wound therapy faces significant challenges due to the complexity of the wound microenvironment, especially dysregulated immune cell responses and persistent pro-inflammatory sate. Targeting immune cells to reverse pathological wound conditions has increasingly become a promising strategy to promote diabetic wound healing. It has been reported that prolonged memory to acute inflammation sensitizes epidermal stem cells (EpSCs) to tissue damage. The increasing importance of interactions between immune cells and tissue stem cells has raised interest in the potential of EpSCs to induce inflammatory adaptations in diabetic wounds, and meanwhile, the inflammation memory patterns also provide new insight in EpSCs for tissue repair. Here, bioinspired cell-derived mimetic nanovesicles (MNVs) were obtained from inflammation memory-activated EpSCs. LPS treatment could trigger acute inflammation response and activate inflammation memory. MNVs derived from LPS-pretreated EpSCs (LEM) can effectively promote diabetic wound healing by manipulating crucial neutrophil regulatory mechanisms. The in vitro and in vivo studies demonstrated that LEM could stimulate neutrophil mitochondrial metabolic reprogramming, overcome phenotypic switching deficiency of neutrophils, and skew neutrophils toward N2 anti-inflammatory phenotype via regulating miR-193a-5p/TLR4/ JNK/P38 MAPK pathways in diabetic models. Our findings highlighted the great potential of inflammation memory in EpSCs, and also provided an alternative for diabetic wound treatment.

Diabetes mellitus, a pervasive chronic metabolic disorder, is often associated with complications such as impaired wound healing. Various factors, most notably vascular deficiency, govern the wound repair process in diabetic patients, significantly impeding diabetic wound healing; therefore, angiogenesis and its role in diabetic wound repair have emerged as important areas of research. This review aims to delve into the mechanisms of angiogenesis, the effects of diabetes on angiogenesis, and the association between angiogenesis and diabetic wound repair. This will ultimately offer valuable guidance regarding the ideal timing of diabetic wound treatment in a clinical setting.

The balance of stem cell populations is essential for the maintenance, renewal, and repair of the mammalian epidermis. Here, we report that CD4, which is a typical marker of helper T cells, monocytes, macrophages, and dendritic cells, is also expressed on murine K5+ keratinocytes. Lineage tracing of CD4+ cells reveals that their epidermal progeny has self-renewal abilities and clonogenic potential. The progeny of CD4+ epidermal cells contributes to epidermal renewal and progressively colonizes the interfollicular epidermis and hair follicles with age, thereby developing to all epidermal lineages. Wound healing studies furthermore show that the progeny of CD4+ epidermal cells accumulates at wound sites. Finally, using CD4 knockout mice we demonstrate that CD4 expression is essential for maintaining fast-cycling epidermal stem cells during homeostasis and that CD4 loss mitigates the age-related decline in wound repair capacity. Collectively, our data support the conclusion that CD4 expression is required for long-term maintenance of the epidermal stem cell balance.

3D printed titanium scaffold has promising applications in orthopedics. However, the bioinert titanium presents challenges for promoting vascularization and tissue growth within the porous scaffold for stable osteointegration. In this study, a modular porous titanium scaffold is created using 3D printing and a gradient-surface strategy to immobilize QK peptide on the surface with a bi-directional gradient distribution. This design featured high peptide density in the interior and low peptide density on both ends, aiming to induce cell migration from ends to interior and subsequently enhance vascularization and osteointegration within the scaffold. In vitro results showed that besides the inherent bioactivity, the gradient distribution of QK positively correlated with endothelial cell migration and promoted angiogenesis. In vivo assay was performed by a segmental bone defect model in rabbit and a spine repair model in sheep. Various staining and Micro-CT results demonstrated that compared to that with uniformly QK-functionalized surface, the scaffold with bi-directional gradient QK-functionalized surface (Ti-G) significantly encouraged new tissue growth toward the interior of the scaffold, subsequently facilitated angiogenesis and osteointegration. This study provides an effective strategy for enhancing the bioactivity of peptide-functionalized scaffolds through the concept of bi-directional gradients, and holds potential for various 3D printed scaffolds.

Wound healing is a complex and multistep biological process that involves the cooperation of various cell types. Programmed cell death, including apoptosis and necrotizing apoptosis, plays a crucial role in this process. Apoptosis, a controlled and orderly programmed cell death regulated by genes, helps eliminate unnecessary or abnormal cells and maintain internal environmental stability. It also regulates various cell functions and contributes to the development of many diseases. In wound healing, programmed cell death is essential for removing inflammatory cells and forming scars. On the other hand, necroptosis, another form of programmed cell death, has not been thoroughly investigated regarding its role in wound healing. This review explores the changes and apoptosis of specific cell groups during wound healing after an injury and delves into the potential underlying mechanisms. Furthermore, it briefly discusses the possible mechanisms linking wound inflammation and fibrosis to apoptosis in wound healing. By understanding the relationship between apoptosis and wound healing and investigating the molecular mechanisms involved in apoptosis regulation, new strategies for the clinical treatment of wound healing may be discovered.

Hydrogels, with their high water content and flexible nature, are a promising class of medical dressings for combating bacterial wound infections. However, their development has been hindered by low sterilization efficiency. Here, this issue is addressed by designing a peptide hydrogel that assembles ordered metal-organic framework (MOF) nanoparticles with photocatalytic bactericidal activity. Specifically, a short peptide, Nap-Gly-Phe-Phe-His (Nap-GFFH), is used to induce the assembly of zinc-imidazolate MOF (ZIF-8) into a hydrogel (NHZ gel). This innovative structure integrates three key features: 1) ZIF-8 nanoparticles are encapsulated within the hydrogel, overcoming their inherent brittleness, insolubility, and limited moldability; 2) the ordered ZIF-8 structure enhances charge transfer, enabling efficient generation of reactive oxygen species (ROS); and 3) ZIF-8 simultaneously improves the photocatalytic bactericidal efficiency and mechanical properties of the hydrogel. The NHZ gel demonstrates remarkable antibacterial performance, achieving >99.9% and 99.99% inactivation of Escherichia coli and Staphylococcus aureus, respectively, within 15 min of simulated solar radiation. Additionally, the NHZ gel exhibits excellent biocompatibility, water retention, and exudate absorption, highlighting its broad potential for wound healing.

Foot ulcers are amongst the most prevalent complications of diabetes, known for their delayed healing process. Recent research indicates that the transcription factor forkhead box M1 (FOXM1) plays a role in promoting diabetic ulcer repair. However, the precise mechanisms underlying FOXM1 functions in this context remain unclear. This study aimed to clarify the role of tripartite motif-containing protein 72 (TRIM72)-mediated endoplasmic reticulum stress in FOXM1 promotive effects. Immunohistochemistry revealed that FOXM1 expression was significantly reduced in the lesion tissues of diabetic foot ulcer patients. In vitro experiments revealed a decrease in FOXM1 expression in cultured dermal fibroblasts under high glucose conditions. Activating FOXM1 with a plasmid accelerated the proliferation, migration, and differentiation of dermal fibroblasts and mitigated endoplasmic reticulum stress under high glucose conditions. Additionally, ChIP and luciferase reporter gene assays confirmed that FOXM1 suppressed TRIM72 expression transcriptionally by binding to its promoter. Furthermore, high glucose induced ubiquitination of adenosine 5'-monophosphate-activated protein kinase alpha (AMPKα), whilst inactivation of AMPKα signalling reversed the aforementioned effects of FOXM1 on cells. Finally, the FOXM1-overexpressing plasmid was transfected in vivo, which promoted wound healing in a murine diabetic ulcer model. In conclusion, FOXM1 reduces endoplasmic reticulum stress by inhibiting TRIM72-mediated AMPKα ubiquitination, thereby accelerating the healing of diabetic ulcers.

Metals are vital in human physiology, which not only act as enzyme catalysts in the processes of superoxide dismutase and glucose phosphorylation, but also affect the redox process, osmotic adjustment, metabolism and neural signals. However, metal imbalances can lead to diseases such as diabetes, which is marked by chronic hyperglycemia and affects wound healing. The hyperglycemic milieu of diabetes impairs wound healing, posing significant challenges to patient quality of life. Wound healing encompasses a complex cascade of hemostasis, inflammation, proliferation, and remodeling phases, which are susceptible to disruption in hyperglycemic conditions. In recent decades, metals have emerged as critical facilitators of wound repair by enhancing antimicrobial properties (e.g., iron and silver), providing angiogenic stimulation (copper), promoting antioxidant activity and growth factor synthesis (zinc), and supporting wound closure (calcium and magnesium). Consequently, research has pivoted towards the development of metal ion-based therapeutics, including innovative formulations such as nano-hydrogels, nano-microneedle dressings, and microneedle patches. Prepared by combining macromolecular materials such as chitosan, hyaluronic acid and sodium alginate with metals, aiming at improving the management of diabetic wounds. This review delineates the roles of key metals in human physiology and evaluates the application of metal ions in diabetic wound management strategies.

Epidermal stem cells (ESCs) are primarily located in the basal layer of the epidermis and play a crucial role in wound healing. ESCs-derived exosomes (ESCs-Exo) are emerging as promising candidates for skin regeneration and wound healing. However, the underlying mechanisms remain unclear. This study aims to investigate the role and mechanisms of ESCs-Exo in promoting the proliferation, migration, and collagen synthesis of human skin fibroblasts (HSFBs).

This study generated, isolated, and characterized ESC-Exos. The effects of ESCs-Exo on the proliferation of human skin fibroblasts (HSFBs) were detected via Cell Counting Kit-8 (CCK8), 5-Ethynyl-2'-deoxyuridine (EdU), and Proliferating Cell Nuclear Antigen (PCNA) and Marker of Proliferation Ki-67 (MKI67) gene expression methods. The effect of ESCs-Exo on the migration of HSFBs was detected via a transwell assay and a scratch test. The concentrations of collagen secreted by the HSFBs and the mRNAs of the two kinds of collagen expressed by the HSFBs were analyzed. We also analyzed the phosphorylation of Protein Kinase N1 (PKN1) and the expression of cyclins via western blotting. Finally, the effect of ESCs-Exo on wound healing was verified by animal experiments, and the key genes and signaling pathways of ESCs-Exo were excavated by transcriptomic analysis.

Western blotting revealed that the exosomes of ESCs highly expressed established markers such as Alix, CD63, and CD9. ESC-Exos significantly promoted HSFB proliferation and migration in a dose-dependent manner, as well as HSFB collagen synthesis, and effectively increased the ratio of collagen III/I. In addition, bioinformatics analysis showed that the expression of key gene C-X-C motif chemokine ligand 9 was lower in the ESCs-Exo group, which may promote wound healing by regulating PKN1-cyclin and tumor necrosis factor signaling pathways. Animal experiments demonstrated that ESCs-Exo could reduce inflammation and accelerate wound healing.

In this study, we found that ESCs-Exo may improve wound healing by promoting the proliferation and migration of HSFBs.

Background: Burns are a global public health issue and a major cause of disability and death around the world. Stem cells, which are the undifferentiated cells with the potential for indefinite proliferation and multilineage differentiation, have the ability to replace injured skin and facilitate the wound repair process through paracrine mechanisms. In light of this, the present study aims to conduct a bibliometric analysis in order to identify research hotspots of stem cell-related burns and assess global research tendencies. Methods: To achieve this objective, we retrieved scientific publications on burns associated with stem cells covering the period from January 1, 1978, to October 13, 2022, from the Web of Science Core Collection (WoSCC). Bibliometric analyses, including production and collaboration analyses between countries, institutions, authors, and journals, as well as keyword and topic analyses, were conducted using the bibliometrix R package, CiteSpace, and VOSviewer. Results: A total of 1648 burns associated with stem cell documents were published and listed on WOSCC. The most contributive country, institution, journal, and author were the United States, LV Prasad Eye Institute, Burns, and Scheffer C.G. Tseng, respectively. More importantly, combined with historical direct citation network, trend topic analysis, keyword co-occurrence network, and substantial literature analysis, we eventually summarized the research hotspots and frontiers on burns associated stem cell reasearch. Conclusion: The present study obtained deep insight into the developing trends and research hotspots on burns associated with stem cells, which arouses growing concerns and implies increasing clinical implications. The mechanism and therapeutics of epidermal stem cells (ESCs) for burn wounds and the mechanism of mesenchymal stem cells (MSCs) and MSC-derived exosomes for burns wounds are two research hotspots in this field.

Cold temperatures have been shown to slow skin wound healing. However, the specific mechanisms underlying cold-induced impairment of wound healing remain unclear. Here, we demonstrate that small extracellular vesicles derived from cold-exposed mouse plasma (CT-sEVs) decelerate re-epithelialization, increase scar width, and weaken angiogenesis. CT-sEVs are enriched with miRNAs involved in the regulation of wound healing-related biological processes. Functional assays revealed that miR-423-3p, enriched in CT-sEVs, acts as a critical mediator in cold-induced impairment of angiogenic responses and poor wound healing by inhibiting phosphatase and poly(A) binding protein cytoplasmic 1 (PABPC1). These findings indicate that cold delays wound healing via miR-423-3p in plasma-derived sEVs through the inhibition of the ERK or AKT phosphorylation pathways. Our results enhance understanding of the molecular mechanisms by which cold exposure delays soft tissue wound healing.

Temperature detection is particularly important in the medical and scientific fields. Although there are various temperature detection methods, most of them focus on broad temperature detection, and basic research in specific fields, especially the detection of subtle temperature changes (32-34 °C) during wound infection, is still insufficient. For this purpose, a novel colorimetric temperature sensing probe is designed in this paper, which can quickly and intuitively respond to small temperature changes within a specific range through color changes. In this paper, hyperbranched polyethyleneimine (HPEI) was modified by isobutyrylation to prepare hyperbranched temperature-sensitive polymer (HPEI-IBAm). And it was combined with gold nanoparticles (AuNPs) prepared by a sodium citrate reduction method to construct an HPEI-IBAm-AuNP colorimetric probe. The probe exhibits excellent stability, even at salt concentrations of up to 12 g/L, thanks to the abundant amino functional groups and the large steric hindrance effect unique to HPEI-IBAm. In particular, the temperature detection range of the probe is precisely locked within 32-34 °C, enabling it to respond quickly and accurately to small temperature changes of only 2 °C. This feature is perfectly suited to the practical needs of temperature detection in infected wounds. The linear fitting coefficient of the temperature response is as high as 0.9929, ensuring the accuracy of the test results. The detection performance of the probe remained highly consistent over 10 cycles, fully proving its excellent reusability and durability. In addition, a flexible colorimetric sensor was prepared by combining the probe with polydimethylsiloxane (PDMS) film. This sensor is capable of rapidly detecting human skin temperature in real time, achieving an accuracy of 99.07% to 100.61%. It can provide a possible solution to the challenges of delayed and difficult temperature detection caused by different body parts and uneven surfaces, among others. This demonstrates its extensive practical value and potential, and it is expected to be further applied in the monitoring of wound infections.

Tendon stem/progenitor cells (TSPCs) are crucial for tendon repair, regeneration, and homeostasis. Dysfunction of TSPCs, due to aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, contributes to tendinopathy. Unfortunately, the effectiveness of conventional subcutaneous injection targeting at suppressing JAK/STAT signaling pathway is limited due to the passive diffusion of drugs away from the injury site. Herein, a novel poly-gamma-glutamic acid (γ-PGA) dual-barb microneedle (MN) path loaded with TSPCs-derived nanovesicles (NVs) containing JAK/STAT inhibitor WP1066 (MN-WP1066-NVs) for tendinopathy treatment is designed. The dual-barb design of the MN ensures firm adhesion to the skin, allowing for sustained and prolonged release of WP1066-NVs, facilitating enhanced TSPCs self-renewal, migration, and stemness in tendinopathy. In vitro and in vivo experiments demonstrate that the degradation of γ-PGA patch tips facilitates the gradual release of WP1066-NVs at the lesion site. This release alleviates inflammation, suppresses extracellular matrix degradation, and restores normal tendon histological structure by inhibiting the JAK/STAT pathway. These findings suggest that the multifunctional dual-barb MN patch offers a novel and effective therapeutic strategy for tendinopathy treatment.

In this review we discuss how the mammalian interfollicular epidermis forms during development, maintains homeostasis, and is repaired following wounding. Recent studies have provided new insights into the relationship between the stem cell compartment and the differentiating cell layers; the ability of differentiated cells to dedifferentiate into stem cells; and the epigenetic memory of epidermal cells following wounding.

Low back pain (LBP) was commonly induced by intervertebral disc degeneration (IVDD), which is accompanied by the loss of disc height and osteophyte generation. Cell-based therapy is a promising treatment for preventing the degeneration of interverbral disc. In our study, allogeneic fibroblasts are shown to ameliorate intervertebral disc degeneration by reducing osteophytes in rabbits.

We established a rabbits-derived fibroblast (Rab-Fib) which could be expanded in vitro and constructed puncture-induced intervertebral disc degeneration rabbit model. Histologic and imaging examinations and analyses were performed after 2 weeks, 3 months, and 12 months.

Our data indicate that stable and reliably-extracted allogeneic fibroblasts can effectively ameliorate intervertebral disc degeneration by reducing osteophytes.

Our study provides a basis for advancing the further translation of fibroblasts in intervertebral disc therapy.

Large skin wounds, with extensive surface area and deep vertical full-thickness involvement, can pose significant challenges in clinical settings. Traditional routes for repairing skin wounds encompass three hallmarks: 1) scab formation for hemostasis; 2) proliferation and migration of epidermal cells for wound closure; 3) proliferation, migration, and functionalization of fibroblasts and endothelial cells for dermal remodeling. However, this route face remarkable challenges to healing large wounds, usually leading to disordered structures and loss of functions in the regenerated skin, due to limited control on the transition among the three stages. In this work, an implantable bioelectronics is developed that enables the synchronization of the three stages, offering accelerated and high-quality healing of large skin wounds. The system efficiently electro-transfect local cells near the wounds, forcing cellular proliferation, while providing a 3D porous environments for synchronized migration of epidermal and dermal cells. In vivo experiments demonstrated that the system achieved synchronous progression of multiple layers within the wounds, leading to the reconstruction of a complete skin structure similar to healthy skin, which presents a new avenue for the clinical translation of large wound healing.

During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.

Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood-feeding. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. We demonstrate through single cell RNA sequencing and murine genetics that wildtype animals infested with EV-deficient Ixodes scapularis display a unique population of keratinocytes with an overrepresentation of pathways connected to wound healing. Tick feeding affected keratinocyte proliferation in a density-dependent manner, which relied on EVs and dendritic epidermal T cells (DETCs). This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor (KGF) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that impairs the integrity of the epithelial barrier, contributing to ectoparasite fitness.