Hydrogen sulfide (H2S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo. This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-(l-lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H2S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H2S release. After mixing and gelling, H2S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H2S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H2S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H2S release for accelerating the infected wound healing.

Wound infections are one of the major threats to human health, accounting for millions of deaths annually. Real-time monitoring, accurate diagnosis, and on-demand therapy are crucial to minimizing complications and saving lives. Herein, we propose a "monitor-and-treat" strategy for infected wound management by integrating the emerging development of bacterio-therapeutics and bio-optics. The upper layer consists of gelatin methacryloyl (GelMA)-collagen III methacryloyl (Col3MA) (GC), Reuterin (Reu) isolated from the probiotic Lactobacillus reuteri (L. reuteri) and microfluidic safflower polysaccharide (SPS)@GelMA microspheres using 3D printing technology. The lower layer is made of acryloylated glycine (ACG) hydrogel with tissue adhesion capability, which enables the hydrogel to adapt to the movement and stretching of the skin. By integrating temperature-sensitive polydimethylsiloxane (PDMS) optical fibers, the ACG-GC/Reu/SPS-PDMS hydrogel could accurately and steadily sense and send wound temperature information to intelligent devices for real-time monitoring of the healing status ("monitor"). The double-layered hydrogel not only inhibited bacterial survival and colonization (97.4 % against E. coli and 99 % against S. aureus), but also exhibited remarkable hemostatic properties. Furthermore, it was conducive to L929 cell proliferation and pro-angiogenesis, and promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype, therefore creating a favorable immune microenvironment at the wound site. Animal experiments using SD rats and Bama minipigs demonstrated that this hydrogel promoted wound closure, directed polarization to M2 macrophages, alleviated inflammation, enhanced neovascularization, therefore accelerating infected wound healing ("treat"). In addition, RNA-Seq analysis revealed the mechanism of action of ACG-GC/Reu/SPS-PDMS hydrogel in modulating key signaling pathways, including down-regulation of AMPK, IL-17, and NF-κB signaling pathways, activation of NLRP3 inflammatory vesicles, and enrichment of MAPK, TGF-β, PI3K-Akt, TNF, and VEGF signaling pathways. The modulation of these signaling pathways suggests that hydrogels play an important role in the molecular mechanisms that promote wound healing and tissue regeneration. Therefore, the design of this study provides an innovative and multifunctional bandage strategy that can significantly improve pathologic diagnosis and wound treatment.

Moisture induced by wound exudate is crucial throughout the wound repair process. The dressing directly affects the absorption, permeation, and evaporation of the wound exudate. However, most dressings in clinical often result in excessive dryness or moisture of wound due to their monotonous structure and function, leading to ineffective thermodynamic control of evaporation enthalpy. Herein, a hydrogel-based nonwoven dressing (Gel-Fabric) with asymmetric amphiphilic surface and persistent microscopic porous structure is constructed by integrating intrinsic hydrophilic absorbent hydrogel fibers and hydrophobic ultrafine PET fibers. The novel Gel-Fabric facilitates rapid vertical drainage of wound exudate through the capillary effect and Laplace pressure synergy. Additionally, dynamic stepwise moisture management is also achieved by regulating the vaporization enthalpy of exudate. In vivo experiments confirm that Gel-Fabric significantly promotes wound healing, vascularization, and endothelialization, achieving a higher healing rate than ordinary dressings. Furthermore, compared to the clinical dressings, Gel-Fabric significantly reduces the frequency of dressing changes, offering improved outcomes for patients and more efficient wound management for healthcare providers.

Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored. Despite significant advances in therapeutic strategies, effective management of large chronic skin wounds remains a clinical challenge. Dermal fibroblasts are the primary cell type responsible for remodeling the extracellular matrix (ECM) in wound healing. Here, we investigated whether ECM derived from exogenous fibroblasts, in combination with keratinocytes, promoted scarless cutaneous wound healing. To overcome the limited lifespan of primary dermal fibroblasts, we established reversibly immortalized mouse dermal fibroblasts (imDFs), which were non-tumorigenic, expressed dermal fibroblast markers, and were responsive to TGF-β1 stimulation. The decellularized ECM prepared from both imDFs and primary dermal fibroblasts shared similar expression profiles of extracellular matrix proteins and promoted the proliferation of keratinocyte (iKera) cells. The imDFs-derived ECM solicited no local immune response. While the ECM and to a lesser extent imDFs enhanced skin wound healing with excessive fibrosis, a combination of imDFs-derived ECM and iKera cells effectively promoted the re-epithelization and scarless healing of full-thickness skin wounds. These findings strongly suggest that dermal fibroblast-derived ECM, not fibroblasts themselves, may synergize with keratinocytes in regulating scarless healing and re-epithelialization of skin wounds. Given its low immunogenic nature, imDFs-derived ECM should be a valuable resource of skin-specific biomaterial for wound healing and skin tissue engineering.

The pathological microenvironment in diabetic wounds is delineated by heightened inflammatory responses and persistent proinflammatory macrophage activity, which significantly hinders the wound healing process. Exogenous electrical stimulation (ES), by modulating the electric field distribution in wounds, has shown significant potential in treating inflammatory wounds. However, this approach relies on additional power sources and complex circuit designs. Here, a bionic neuro-immuno-regulatory (BNIR) system was proposed for reshaping the endogenous electric fields (EFs) through collecting ion flow. The BNIR system comprises microporous structure scaffolds and nanosheets, enabling swift biofluid collection and electrical signal transmission, with the ability to promote cell proliferation and migration and exhibit antioxidant properties. More importantly, the BNIR system induced the transition of M1 macrophages to M2 macrophages through neuro-immuno-regulatory. In diabetic rat skin wounds, the BNIR system significantly enhanced healing by simultaneously neuro-immuno-regulatory, promoting angiogenesis, scavenging ROS, and facilitating tissue remodeling. This work aims to advance the development of a bionic system for electrosensitive tissue repair.

The hemostatic, inflammatory, proliferative, and remodeling phases of healing require precise spatiotemporal coordination and orchestration of numerous biological processes. As the primary energy generators in the cell, mitochondria play multifunctional roles in regulating metabolism, stress reactions, immunity, and cell density during the process of tissue regeneration. Mitochondrial dynamics involves numerous crucial processes, fusion, fission, autophagy, and translocation, which are all necessary for preserving mitochondrial function, distributing energy throughout cells, and facilitating cellular signaling. Tissue regeneration is specifically associated with mitochondrial dynamics due to perturbations of Ca2+, H2O2 and ROS levels, which can result in mitochondrial malfunction. Increasing evidence from multiple models suggests that clinical interventions or medicinal drugs targeting mitochondrial dynamics could be a promising approach. This review highlights significant advances in the understanding of mitochondrial dynamics in tissue regeneration, with specific attention on mitochondria-targeting biomaterials that accelerate multiple tissues' regeneration by regulating mitochondrial metabolism. The innovations in nanomaterials and nanosystems enhance mitochondrial-targeting therapies are critically examined with the prospects of modulating mitochondrial dynamics for new therapies in regenerative engineering.

Wound healing in chronic diabetic patients remains challenging due to the multiple types of cellular dysfunction and the impairment of multidimensional microenvironments. The physical signals of structural anisotropy offer significant potential for orchestrating multicellular regulation through physical contact and cellular mechanosensing pathways, irrespective of cell type. In this study, we developed a highly oriented anisotropic nanofiber hydrogel designed to provide directional guidance for cellular extension and cytoskeletal organization, thereby achieving pronounced multicellular modulation, including shape-induced polarization of macrophages, morphogenetic maturation of Schwann cells, oriented extracellular matrix (ECM) deposition by fibroblasts, and enhanced vascularization by endothelial cells. Additionally, we incorporated a VEGF-mimicking peptide to further reinforce angiogenesis, a pivotal phase that interlocks with immune regulation, neurogenesis, and tissue regeneration, ultimately contributing to optimized inter-microenvironmental crosstalk. In vivo studies validated that the anisotropic bioactive nanofiber hydrogel effectively accelerated diabetic wound healing by harnessing the triadic synergy of the immune-angiogenic-neurogenic microenvironments. Our findings highlight the promising potential of combining physical and bioactive signals for the modulation of various cell types and the refinement of the multidimensional microenvironment, offering a novel strategy for diabetic wound healing.

Identifying factors mediating adipose-derived stem cells (ADSCs)-induced endothelial cell angiogenesis in hypoxic skin flap tissue is critical for reconstruction. While the paracrine action of VEGF by adipose-derived stem cells (ADSCs) is established in promoting endothelial cell angiogenesis, the role of FGF2 and its regulatory mechanisms in ADSCs paracrine secretion remains unclear.

We induced hypoxia and examined the expression level of FGF2 in ADSCs using ELISA, qRT-PCR, and western blotting. Proliferation of ADSCs under hypoxia was assessed using a CCK-8 assay. Co-culture experiments of hypoxia-induced ADSCs with vascular endothelial cells were conducted, and migration and tube formation abilities were evaluated through wound healing assays, transwell cell migration, and tube formation experiments.

Hypoxia treatment induced significant upregulation of FGF2 expression in ADSCs, along with enhanced cell proliferation. Co-culture of hypoxia-induced ADSCs with vascular endothelial cells showed increased migration and tube formation abilities of endothelial cells. Knockdown of FGF2 inhibited these processes, while overexpression of miR-103-3p mimics in ADSCs suppressed endothelial cell migration and tube formation. FGF2 is a direct target of miR-103-3p in ADSCs. miR-103-3p/FGF2 axis regulates ADSCs on the biological activity of co-cultured vascular endothelial cells. Moreover, in the ischemic skin flap nude mouse model, ADSCs injection showed increased blood vessel formation and reduced flap necrosis, with the most significant improvement observed with ADSCs of miR-103-3p inhibitor overexpressed.

Hypoxia induces paracrine secretion of FGF2 from ADSCs, which enhances endothelial cell angiogenesis. FGF2 expression is regulated by miR-103-3p in ADSCs. The miR-103-3p/FGF2 axis induces endothelial cell migration and angiogenesis and finally modulates ischemic skin flap repair in nude mice in vivo.

Fibrosis is the pathological outcome of many chronic inflammatory diseases, affecting various human organs. It is a significant contributor to global morbidity and mortality that affects nearly half of the elderly population. Pirfenidone (PFD) and nintedanib are approved by the FDA for treating pulmonary fibrosis, but these treatments are associated with poor tolerability and limited efficacy. Moreover, no antifibrotic drugs are approved for other fibrosis-related diseases, highlighting an urgent unmet medical need for more effective therapies. Here we report the in vivo pharmacological activities of AK3280, a novel, orally bioavailable small molecule designed to enhance pharmacokinetics, antifibrotic activity, and tolerability over PFD. AK3280 demonstrated antifibrotic effects across multiple organs, including the lungs, liver, heart, and skin, in various animal models. These results suggest that AK3280 holds promise as a clinically beneficial antifibrotic therapy for a range of fibrotic diseases, especially pulmonary, hepatic, cardiac, and skin fibrosis.

Wound healing is a complex natural process in which tissue requires recovering injured tissue cells. Helix aspersa has a high nutritional value and is considered a rich natural source of antioxidants and anti-inflammatory agents. So, this study aimed to assess the effect of soft tissue crude extract and mucous of H. aspersa topically applied as a gel for 12 days. The wounds were observed and photographed twice a week. The inflammatory, oxidative stress markers and matrix metalloproteinases were evaluated in skin tissue homogenate and CD3+ and CD69+ T lymphocytes were detected in wound tissue. Data showed that a comparison of applying soft tissue crude extract and mucous of H. aspersa to skin wounds enhanced the healing process, resulting in a significant decrease in dermal inflammation compared to untreated mice. Also, they significantly increased the antioxidant enzyme activities with reduced malondialdehyde (MDA) levels in wound tissues. The levels of matrix metalloproteases-2 and -9 were significantly decreased and the immune status was enhanced in the wound environment by increasing proportions of CD3+ and CD69+ T lymphocytes. H. aspersa mucous and soft tissue crude extract are viable substitutes for synthetic topical wound therapies with anti-inflammatory, antioxidant, and immunomodulatory potencies, with a preference for the crude soft tissue extract based on the outcomes.

Release of growth factors in the tissue microenvironment is a critical process in the repair and regeneration of periodontal tissues, regulating fibroblast behavior and phenotype. As a result of the complex architecture of the periodontium, distinct fibroblast populations in the periodontal ligament and gingival connective tissue exist in close proximity. Growth factor therapies for periodontal regeneration have gained traction, but quantification of their effects on multiple different fibroblast populations that are required for repair has been poorly investigated. In this study, we examined the effects of TGF-β1, TGF-β3, FGF-2, and FGF-9 on human gingival fibroblasts (hGF) and human periodontal ligament cells (hPDL), as well as the combined effects of TGF-β3 and FGF-2. We show that FGF-2 enhances cell migration while TGF-β1 and TGF-β3 promotes matrix production, and TGF-β1 promotes fibroblast to myofibroblast transition. Interestingly, the combination of TGF-β3 and FGF-2, acting through both p-SMAD3 and p-ERK pathways, mitigates the inhibitory effects of TGF-β3 on migration in hPDL cells, suggesting synergistic and complimentary effects of FGF-2 and TGF-β3. Additionally, fibronectin production in hGF increased when treated with the combined TGF-β3+FGF-2 compared to FGF-2 alone, indicating that the effects of TGF-β3 in promoting extracellular matrix production are still active in the combined treatment condition. Finally, our study highlights that FGF-9 did not influence migration, α-SMA expression, or extracellular matrix production in either cell type, emphasizing the unique roles of specific growth factors in cellular responses. The synergistic effects observed with combined TGF-β3 and FGF-2 treatments present promising avenues for further research and clinical advancements in regenerative medicine.

The management of diabetic wounds (DW) is a significant challenge within the medical field. Effectively regulating the levels of reactive oxygen species (ROS) at the wound site and orchestrating the inflammatory response are effective strategies for DW treatment. In this study, a novel hydrogel was developed by cross-linking polyboronic acid-modified carboxymethyl chitosan with herbal active ingredient rosmarinic acid (RA), an active herbal ingredient, through dynamic boronic esters formation. In this RA hydrogel (RAgel), RA serves both as an active pharmaceutical ingredient and as a linker for the creation of a dynamic covalent hydrogel, which can decrease the potential toxicity of chemical crosslinking agents and improve the utilization of RA. RAgel demonstrated potential for controlling RA loading and responsiveness to ROS and glucose levels in a diabetic wound environment. Additionally, the intrinsic antioxidant and antibacterial properties of RA were effectively preserved and enhanced upon integration into RAgel. Furthermore, RAgel not only promoted the migration of L929 cells, a key aspect of tissue repair, but also induced M2 polarization in macrophages,while inhibiting the secretion of pro-inflammatory cytokines. In a murine model of diabetic wound healing, RAgel significantly enhanced the proliferation of both the epidermal and granulation tissues. It also exerts a marked anti-inflammatory effect and promotes collagen deposition, thereby expediting the overall wound healing process. The reported RAgel formulation has potential to address the complex challenges associated with diabetic wound management.

The healing of infected wounds is a complex and dynamic process requiring tailored treatment strategies that address both antimicrobial and reparative needs. Despite the development of numerous drugs, few approaches have been devised to optimize the timing of drug release for targeting distinct phases of infection control and tissue repair, limiting the overall treatment efficacy. Here, a stimuli-responsive microsphere encapsulating dual drugs was developed to facilitate differential drug release during distinct phases of antibacterial and repair promotion, thereby synergistically enhancing wound healing. Specifically, zeolite imidazolate backbone in poly (lactic-co-glycolic acid) (PLGA) microsphere was employed for the encapsulation of ciprofloxacin (CIP), responding to acidic environment of bacteria and releasing antibiotic for antibacterial therapy. Meanwhile, curcumin (CUR) encapsulated in PLGA exhibited a gradual release profile, contributing to synergistic antibacterial effects. During the tissue repair phase, near-infrared light stimulation of Fe3O4 embedded in PLGA generated heat, elevating the temperature to the glass transition point of PLGA, which significantly enhanced the release of CUR thereby promoting tissue repair. In vitro experiments demonstrated that the release of CIP and CUR achieved significant antibacterial effects in the early stages of treatment. Additionally, CUR could effectively enhance fibroblast migration and proliferation. In vivo studies using a mouse abscess model revealed that the microspheres exhibited remarkable antibacterial and wound-healing capabilities, effectively enhancing the re-epithelialization of wound tissue and reducing the infiltration of inflammatory cells. This study provides novel strategies for constructing drug delivery systems that match dynamic stages of wound healing, offering improved therapeutic outcomes for infected wounds.

Wound healing is a complex but precise physiological process. Howener, existing treatments are often difficult to meet the needs of different wound healing. With the background that exogenous electrical stimulation (ES) has been proven to be effective in regulating cell behavior, we constructed a electroactive wound dressing derived from carbon nanotubes (CNT) by electrospinning technology. The scaffold has a moderate hydrophilicity, which benefits to collecting of effusion, adhering to the wound site, and safely removing. Furthermore, the oriented structure has the potential to promote cell oriented growth, while the coupling of endogenous electric field (EFs) and ES could effectively regulate the phenotype of macrophages and reshape the immune microenvironment. At the same time, the active electrical stimulation promotes the secretion of active factors and the proliferation and migration of fibroblasts and endothelial cells. In vivo assays further confirm that PCL/GE/CNT combined ES strategy can significantly inhibit the early inflammatory response, while promoting vascular regeneration and collagen deposition. RNA sequencing analysis is used to reveal the mechanism at the molecular level. Overall, this study employed a composite strategy of combining CNT with moderately hydrophilic biocompatible nanofibers to achieve ES delivery simply and effectively, significantly improving tissue engineering outcomes. This innovative strategy provides a feasible approach for efficient wound repair, and provides an important experimental basis and theoretical guidance for future development in the field of skin tissue engineering.

Pseudomonas aeruginosa infection is the most common pathogen in burn wound infections, causing delayed wound healing and progression to chronic wounds. Therefore, there is an urgent need to develop antimicrobial agents that can promote wound healing for effectively treating infected wounds.

Using magnetic stirring and ultrasound to synthesize Apt-pM@UCNPmSiO2-Cur-CAZ. The nanosystems were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), and ultraviolet-visible spectrophotometry (UV-Vis). Flow cytometry, bacterial LIVE/DEAD staining and scanning electron microscopy were performed to assess the in vitro antibacterial and anti-biofilm effects of the nanosystems. The wound healing potential and in vivo toxicity of the nanosystems were evaluated in a mouse skin wound model.

The Apt-pM@UCNPmSiO2-Cur-CAZ synthesized exhibited uniform circular shape with a Zeta potential of -0.8 mV. In vitro, Apt-pM@UCNPmSiO2-Cur-CAZ demonstrated superior antibacterial effects compared to standalone antibiotics. Bacteria treated with Apt-pM@UCNPmSiO2-Cur-CAZ showed varying degrees of deformation and shrinkage, resulting in severe damage to the bacterial cells. Additionally, Apt-pM@UCNPmSiO2-Cur-CAZ can inhibit and eradicate bacterial biofilms, while also targeting bacteria for enhanced antibacterial efficacy. Interestingly, the NIR light could enhance the antibacterial and anti-biofilm effects of Apt-pM@UCNPmSiO2-Cur-CAZ due to the photodynamic action. In a mouse skin wound infection model, the nanosystem effectively eliminated wound bacteria, promoting the healing of Pseudomonas aeruginosa-infected wounds without significant toxic effects.

Apt-pM@UCNPmSiO2-Cur-CAZ is a novel targeted nano-delivery system with promising potential in combating Pseudomonas aeruginosa infections, and it may serve as a new therapeutic approach for treating skin wound infections.

This article explores the paradoxic nature of radiation as both a destructive and regenerative force. The article examines the interplay of signaling pathways, immune modulation, and stem cells in tissue regeneration post radiation, emphasizing the roles of key pathways like Wnt, Hedgehog, Notch, and p53. It highlights advancements in low-dose radiation therapy, extracellular vesicles, and stem cell-based interventions. Furthermore, the immune system's dual role in repair and damage is dissected, along with technologies such as artificial intelligence and bioengineered scaffolds that enhance therapeutic outcomes. The article offers a roadmap for integrating therapeutic innovation with regenerative medicine to improve patient outcomes.

Delayed wound healing remains a major challenge in biomedical research, often leading to complications such as scarring, acute trauma, and chronic diseases. Effective wound management is crucial for enhancing treatment outcomes, preventing complications, and promoting tissue regeneration. In response to this need, a variety of polymeric biomaterials have been developed. A growing focus in the field involves the design of bioadhesives and bioactive materials, which offer promising solutions for wound management. Recent advances in materials engineering have led to the development of polymer biomaterials with excellent biocompatibility, strong adhesion to biological surfaces, and bioactive properties that support rapid wound closure and tissue repair. This review discusses the latest progress in the development and application of bioadhesives and bioactive hydrogels for wound management and tissue regeneration, highlighting potential directions for future biomaterial research.

1α,25-Dihydroxyvitamin D3 (VD3), the active form of vitamin D, plays a crucial role in wound healing. In this study, we aimed to investigate the effect of VD3 on the proliferation and differentiation of epidermal stem cells (EpSCs) and monitor its impact on re-epithelialization. We established a murine full-thickness skin defect model and applied four doses of VD3 (0, 5, 50, and 250 ng/mouse/day) to the wounds topically for three days. Immunostaining and flow cytometry confirmed the effect of VD3 on the proliferation and differentiation of EpSCs in wounds. This effect of VD3 (0, 1, 10, and 50 nM) on EpSCs and its possible mechanism were further confirmed in vitro by CCK8, westen blot, immunostaining, and flow cytometry. We found that on day five post-wounding, the means±SD length of the neo-epidermis was 195.88±11.57, 231.84±16.45, 385.80±17.50, and 268.00±8.22 μm in the control, 5, 50, and 250 ng groups, respectively, with a significant difference from the control (all P<0.05). Immunostaining and flow cytometry showed that VD3 improved the proliferation and differentiation of K15+ EpSC (vs control, all P<0.05), K14+ epidermal progenitor cells (vs control, all P<0.05), and K10+ epidermal terminal cells (vs control, all P<0.05) in vivo and in vitro. The PI3K signaling pathway appeared to underlie this response because significant inhibition of the response was found when inhibitors were used to inhibit PI3K. Our study demonstrated that VD3 is a potent promoter of cutaneous wound healing by stimulating EpSC proliferation and differentiation through PI3K activation.

In the corneal wound healing process, epithelial cell re-epithelialization and migration are the critical first steps following an injury. As the disease progresses, orderly regeneration of corneal stromal collagen and mild corneal stromal fibrosis are vital for corneal function reconstruction. Exosomes derived from adipose-derived mesenchymal stem cells (ADSCs-Exos) have emerged as a promising therapy due to their anti-oxidant, anti-apoptosis, and tissue repair properties. In this study, we successfully isolated exosomes via differential centrifugation and verified their effective extraction through transmission electron microscopy and nanoparticle tracking analysis. In vitro, ADSCs-Exos increased corneal epithelial cell migration by 20 % and reduced oxidative damage by 50 %. In addition, ADSCs-Exos demonstrated remarkable wound healing properties in corneal tissue. This effect was attributed to their ability to inhibit apoptosis of corneal stroma cells by upregulating Bax and downregulating Bcl2, reducing the Bax/Bcl2 protein expression ratio from 1 to 0.45. This decrease may subsequently inhibit α-SMA expression, thereby preventing corneal scarring. Overall, this research has elucidated the effects and potential targets of ADSCs-Exos in promoting corneal wound repair, offering a novel and promising approach for treating corneal injuries.

Wound healing is a dynamic process over temporal and spatial scales. Key to repair outcomes are fibroblasts; yet, how they modulate healing across time and in different wound regions remains incompletely understood. By integrating single-cell RNA-sequencing datasets of mouse skin and wounds, we infer that fibroblasts are the most transcriptionally dynamic skin-resident cells, evolving during postnatal skin maturation and rapidly after injury toward distinct late scar states. We show that transcriptional dynamics in fibroblasts are largely driven by genes encoding extracellular matrix and signaling factors. Lineage trajectory inference and spatial gene mapping reveal that Prg4-expressing fibroblasts transiently emerge along early wound edges. Within days, they become replaced by long-lasting and likely noninterconverting fibroblast populations, including Col25a1-expressing and Pamr1-expressing fibroblasts that occupy subepidermal and deep scar regions, respectively, where they engage in reciprocal signaling with immune cells. Signaling inference shows that fibroblast-immune crosstalk repeatedly uses some signaling pathways across wound healing time, whereas use of other signaling pathways is time and space limited. Collectively, we uncovered high transcriptional plasticity by wound fibroblasts, with early states transiently forming distinct microniches along wound edges and in the fascia, followed by stable states that stratify scar tissue into molecularly dissimilar upper and lower layers.

Achieving scar-free skin regeneration in clinical settings presents significant challenges. Key issues such as the imbalance in macrophage phenotype transition, delayed re-epithelialization, and excessive proliferation and differentiation of fibroblasts hinder wound healing and lead to fibrotic repair. To these, we developed an active shrinkage and antioxidative hydrogel with biomimetic mechanical functions (P&G@LMs) to reshape the healing microenvironment and effectively promote skin regeneration. The hydrogel's immediate hemostatic effect initiated sequential remodeling, the active shrinkage property sealed and contracted the wound at body temperature, and the antioxidative function eliminated ROS, promoting re-epithelialization. The spatiotemporal release of LMs (ACEI) during the inflammation phase regulated macrophage polarization towards the anti-inflammatory M2 phenotype, promoting progression to the proliferation phase. However, the profibrotic niche of macrophages induced a highly contractile α-SMA positive state in myofibroblasts, whereas the sustained LMs release could regulate this niche to control fibrosis and promote the correct biomechanical orientation of collagen. Notably, the biomimetic mechanics of the hydrogel mimicked the contraction characteristics of myofibroblasts, and the skin-like elastic modulus could accommodate the skin dynamic changes and restore the mechanical integrity of wound defect, partially substituting myofibroblasts' mechanical role in tissue repair. This study presents an innovative strategy for skin regeneration.

Dermal white adipose tissue (dWAT), distinguished by its origin from cells within the dermis and independence from subcutaneous fat tissue, has garnered significant attention for its non-metabolic functions. Characterized by strong communication with other components of the skin, dWAT mediates the proliferation and recruitment of various cell types by releasing adipogenic and inflammatory factors. Here, we focus on the modulatory role of dWAT at different stages during wound healing, highlighting its ability to mediate the adipocyte-to-myofibroblast transition which plays a pivotal role in the physiology and pathology processes of skin fibrosis, scarring, and aging. This review highlights the regulatory potential of dWAT in modulating wound healing processes and presents it as a target for developing therapeutic strategies aimed at reducing scarring and enhancing regenerative outcomes in skin-related disorders.

Hyperuricemia-related diabetic wounds are notoriously difficult to treat due to elevated uric acid (UA) levels, excessive reactive oxygen species (ROS), and chronic inflammation. Current therapies often fail to address these underlying causes, underscoring the need for innovative approaches that not only clear UA but also mitigate inflammation and promote tissue regeneration. In this study, we developed a polyrotaxane-based microsphere (HPR MS) system conjugated with 4,5-diamino-2-thiouracil (DT) to achieve high-affinity UA clearance without increasing cytotoxicity. By leveraging the molecular motility of the polyrotaxane structure, featuring β-cyclodextrin (β-CD) shuttles along the F-127 axis, we significantly improved the molecular recognition between DT and UA for enhanced UA absorption efficiency. In vitro experiments confirmed that HPR/DT MS rapidly reduced UA levels compared to control groups. Using a type 2 diabetic wound model, HPR/DT MS treatment effectively reduced UA levels, suppressed COX-2 expression, and transformed the immune microenvironment from a pro-inflammatory to a regenerative state in vivo. This was accompanied by enhanced M2 macrophage polarization, angiogenesis, and improved blood perfusion, resulting in accelerated wound healing. Overall, these findings highlight HPR/DT MS as a promising therapeutic strategy for hyperuricemia-related diabetic wounds, targeting the core pathological factors to improve wound repair.

Surgical removal of the impacted third molar is a routinely employed procedure in oral surgery, often associated with various complications which affect wound healing. Hyaluronic acid (HA) and freeze-dried (lyophilized) amniotic membrane (AM) have demonstrated the potential to promote wound healing and bone regeneration. These could aid in the healing of the extraction socket post-disimpaction.

To assess the extent of wound healing and bone regeneration in extraction sockets of surgically removed mandibular third molars following intra-socket application of 0.2 % HA gel and 2.5 × 2.5 cm of AM.

45 patients were clinically and radiographically evaluated based on the inclusion and exclusion criteria and were randomized by lottery method into three groups - Group 1, control, Group 2, AM, and Group 3, HA. The pain scores were evaluated using the visual analog scale. The extent of facial swelling, trismus and bone regeneration were assessed at three different time intervals.

A significant difference (p<0.05) in the pain score was observed between the control group and the study groups. The extent of facial swelling and trismus observed was of significance within the groups (p<0.05). Group 2 exhibited significantly improved levels of trabecular bone formation at the third post-operative month (p<0.05).

HA and AM could be potentially useful in improving the post-operative sequelae following surgical removal of mandibular third molars in terms of pain, wound healing, and overall bone regeneration.

Macrophages play a key role in wound healing. Dysfunction of their M0 polarization to M2 leads to disorders of the wound immune microenvironment and chronic inflammation, which affects wound healing. Regulating the polarization of M0 macrophages to M2 macrophages is an effective strategy for treating wound healing. Mesenchymal stem cells (MSCs) deliver endogenous regulatory factors via paracrine extracellular vesicles, which may play a key role in wound healing, and previous studies have shown that apoptotic bodies (ABs) are closely associated with inflammation regression and macrophage polarization. However, the specific regulatory mechanisms involved in ABs remain unknown. In the present study, we designed an MSC-AB (MSC-derived AB)-loaded polycaprolactone (PCL) scaffold, evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro, and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing. Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs, and drives M0 macrophages to program M2 macrophages to regulate inflammation and angiogenesis, thereby synergistically promoting wound healing. This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immune responses.

In the peripheral nervous system, glial cells, known as Schwann cells (SCs), are responsible for supporting and maintaining nerves. One of the most important characteristics of SCs is their remarkable plasticity. In various injury contexts, SCs undergo a reprogramming process that generates specialized cells to promote tissue regeneration and repair. However, in pathological conditions, this same plasticity and regenerative potential can be hijacked. Different studies highlight the activation of the epithelial-mesenchymal transition (EMT) as a driver of SC phenotypic plasticity. Although SCs are not epithelial, their neural crest origin makes EMT activation crucial for their ability to adopt repair phenotypes, mirroring the plasticity observed during development. These adaptive processes are essential for regeneration. However, EMT activation in SCs-derived tumours enhances cancer progression and aggressiveness. Furthermore, in the tumour microenvironment (TME), SCs also acquire activated phenotypes that contribute to tumour migration and invasion by activating EMT in cancer cells. In this review, we will discuss how EMT impacts SC plasticity and function from development and tissue regeneration to pathological conditions, such as cancer.

Oral ulcers, affecting 27.9% of adults, can lead to malnutrition and dehydration, especially in individuals with diabetes, cancer, viral infections, and autoimmune diseases. Existing treatments-including oral films, sprays, frosts, and powders-often fail to be effective due to rapid dilution and clearance in the moist oral environment. This study is the first to investigate the use of Cold Atmospheric Plasma (CAP) for treating oral ulcers and its underlying molecular mechanisms. A novel high-bioavailability, mucoadhesive therapy combining handheld three dimensions (3D) multi-microhole CAP is developed with a nanogel-based pharmaceutical system containing glucose oxidase (GOx) and catalase (CAT), termed GCN. These results showed that both CAP alone and CAP combined with GCN significantly accelerate oral ulcer healing, modulate immune responses, and activate the Epidermal Growth Factor Receptor (EGFR) in acetic acid-induced oral ulcers, outperforming untreated controls and the conventional medication, Watermelon Frost (WF). Furthermore, the CAP+GCN combination enhances therapeutic effects by promoting fibroblast generation. CAP pretreatment also enhances cell permeability and nanoparticle uptake, improving tissue adhesion. These findings are validated in primary Human Gingival Fibroblasts (HGF) and Human Periodontal Ligament Stem Cells (PDLSC) from healthy donors, as well as an oral ulcer model in rats, demonstrating superior biocompatibility and safety.

Non-healing wounds are long-term complications of diabetes mellitus (DM) that increase mortality risk and amputation-related disability and decrease the quality of life. Nitric oxide (NO·)-based treatments (i.e., use of both systemic and topical NO· donors, NO· precursors, and NO· inducers) have received more attention as complementary approaches in treatments of DM wounds. Here, we aimed to highlight the potential benefits of NO·-based treatments on DM wounds through a literature review of experimental and clinical evidence. Various topical NO·-based treatments have been used. In rodents, topical NO·-based therapy facilitates wound healing, manifested as an increased healing rate and a decreased half-closure time. The wound healing effect of NO·-based treatments is attributed to increasing local blood flow, angiogenesis induction, collagen synthesis and deposition, re-epithelization, anti-inflammatory and anti-oxidative properties, and potent broad-spectrum antibacterial effects. The existing literature lacks human clinical evidence on the safety and efficacy of NO·-based treatments for DM wounds. Translating experimental favors of NO·-based treatments of DM wounds into human clinical practice needs conducting clinical trials with well-predefined effect sizes, i.e., wound reduction area, rate of wound healing, and hospital length of stay.

Organ fibrosis, considered as a major global health concern, is a pathological condition often occurring after tissue injury in various organs. The pathogenesis of fibrosis involves multiple phases and multiple cell types. Dopamine is involved in various life activities by activating five receptors (D1, D2, D3, D4, D5). Activation or loss of function of dopamine receptors has been reported to be associated with the fibrosis of several organs, such as ocular, lung, liver, heart, and kidney. In this paper, we review dopamine receptors' potential roles in organ fibrosis and mechanisms by which organ fibrosis develops or decreases when dopamine receptors function is activated or perturbed.

The self-assembled peptide RADA16-I (RADARADARADARADA) has been widely used in biomaterials. However, studies on the practical application of self-assembled peptide hydrogels loaded with bioactive peptides are still insufficient. In this study, we successfully prepared the peptide nanofiber gel RGJ by incorporating the bioactive peptides A8SGLP-1 (G) and Jagged-1 (J) into RADA16-I (R) in specific ratios. The mechanical properties, secondary structure, and microstructure of RGJ were thoroughly characterized using a rheometer, circular dichroism (CD), and transmission electron microscopy (TEM). The results showed that R and RGJ adopted stable β-folded structures at room temperature, and RGJ exhibited a nanofiber mesh structure, confirming its excellent physical properties. Cellular experiments demonstrated that RGJ significantly enhanced the proliferation and migration of HaCaT, L929, and HUVEC cells, with the most pronounced effect observed in HUVEC cells. In the 100 μg/mL RGJ-treated group, cell viability (OD value) reached 1.369, which was significantly higher than that of the control group (0.673) and the R-only group (0.848). The strongest pro-migratory effect was observed in HaCaT cells, with a scratch closure rate of 22.83 %. In vivo experiments showed that the deep second-degree burn wounds of mice in the RGJ gel-treated group healed rapidly by day 17, exhibiting 99.5 % wound closure, compared to 84.02 % in the R gel group, and 73.02 % and 70.97 % in the control and burn cream groups, respectively. Immunohistochemistry and ELISA results further confirmed that RGJ significantly reduced wound and systemic inflammatory responses while promoting the secretion of pro-angiogenic factors VEGF and CD31, revealing its potential mechanism for enhancing burn wound healing. Additionally, RGJ significantly reduced wound scar formation and increased skin collagen deposition, demonstrating a favorable biosafety profile compared to the control group, commercial burn ointment, and the R-only treatment group. In conclusion, the development of the peptide nanofiber gel RGJ holds great potential for wound management applications and lays a foundation for future related research.

Diabetic foot ulcer is a critical complication of diabetes, but the wound microenvironment and its healing process are not completely understood. In this study, we optimized single-cell profiling from sharp debrided ulcers. Our findings demonstrate that healing diabetic foot ulcers were significantly enriched with distinct fibroblasts-expressing genes related to inflammation (CHI3L1, IL6) and extracellular matrix remodeling (ASPN), validating our previous studies on surgically resected ulcers. The race-focused analysis depicted lower expression of key healing-associated genes such as CHIL3L1, matrix metalloproteinase 11 gene MMP11, and SFRP4 in fibroblasts of non-Hispanic Black patients than in those of White patients. In cellular communication analysis, healing-enriched fibroblasts of non-Hispanic Black patients exhibited upregulation of signaling pathways such as WNT, whereas those of White patients showed insulin-like GF and Midkine pathways upregulation. Our findings advocate race as a risk marker of diabetic foot ulcer outcomes, likely reflecting underlying disparities in environmental exposures and access to care that profoundly influence healing markers. Using sharp debrided tissues for single-cell assays, this study highlights the need for in-depth investigations into dysregulated wound healing microenvironments of under-represented racial groups.

The multiple layers of the skin cover and protect our entire body. Among the skin layers, the epidermis is in direct contact with the outer environment and serves as the first line of defense. The epidermis functions as a physical and immunological barrier. To maintain barrier function, the epidermis continually regenerates and repairs itself when injured. Interactions between tissue-resident immune cells and epithelial cells are essential to sustain epidermal regeneration and repair. In this review, we will dissect the crosstalk between epithelial cells and specific immune cell populations located in the epidermis during homeostasis and wound repair. In addition, we will analyze the contribution of dysregulated immune-epithelial interactions in chronic inflammatory diseases.

Fibrosis is a multifactorial process characterized by the excessive accumulation of extracellular matrix (ECM), increased tissue stiffness, and decreased elasticity. This study examined how individual cytokines and a cytokine combination alter collagen production and biomechanics in a 3D in vitro model of the human ECM.

Cultured human fibroblasts were seeded into a circular agarose trough molded in 24 well plates. The fibroblasts aggregated and formed a 3D ring-shaped tissue that synthesized de novo a collagen-rich human ECM complete with collagen fibrils. Unlike existing models, no macromolecular crowders were added, nor artificial scaffolds or exogenous ECM proteins. Rings were treated with TGF-β1, IL-13 or the combination of TGF-β1 and IL-13 for up to 3 weeks. Morphology, histology, collagen, DNA, fibril formation, gene expression and tensile properties of the rings were measured.

As the rings compacted, cellularity and total DNA decreased, whereas total collagen accumulated. TGF-β1 stimulated collagen accumulation and increased ring biomechanics at day 7, but these increases stalled and declined by day 21. When treated with IL-13, a cytokine exclusive to the immune system, there were no significant differences from control. However, when TGF-β1 was combined with IL-13, collagen levels and ring biomechanics increased over the entire three weeks to levels higher than TGF-β1 alone. Gene expression was differentially regulated by cytokine treatment over the entire three weeks suggesting that increased collagen accumulation was not due to upregulation of collagen gene expression.

These results suggest that TGF-β1 requires a second signal, such as IL-13, to sustain the long-term pathological increases in collagen accumulation and biomechanics that can compromise the function of fibrotic tissues.

Diabetic wounds face challenges like infection, prolonged inflammation, and poor vascularization. To address these, we developed an injectable hydrogel for diabetic wound dressing by grafting palmitoyl tetrapeptide-7 (Pal-7) onto chitosan (CS) to form CS/Pal-7 (CP7). Glutaraldehyde (GA) was used to enhance crosslinking between CS, creating the CP7 hydrogel. The hydrogel showed rapid gelation, good mechanical properties, biocompatibility, and strong antibacterial effects. Additionally, stem cells derived from human deciduous teeth (SHED) were loaded into the CP7 hydrogel to form SHED@CP7. This complex promoted human umbilical vein endothelial cell (HUVEC) migration and tube formation, aiding angiogenesis, and induced macrophage polarization toward the M2 phenotype, exerting anti-inflammatory effects. In streptozotocin-induced diabetic mouse wounds, SHED@CP7 significantly improved wound healing with over 95 % wound closure, increased collagen deposition, and reduced tumor necrosis factor-α (TNF-α) expression by approximately 75 % and Interleukin-6 (IL-6) expression by around 81 %. It also increased Interleukin-10 (IL-10) expression by approximately 58 %, modulating the inflammatory microenvironment for regeneration. Moreover, SHED@CP7 enhanced angiogenesis, as shown by a 69 % increase in endothelial cell marker CD31 staining, supporting faster wound healing. These results highlight the potential of SHED@CP7 as an effective treatment for diabetic wounds.

MXenes, with their good biocompatibility, excellent photovoltaic properties, excellent physicochemical properties, and desirable bioactivity, have broad application prospects in the field of tissue regeneration. MXenes have been used in a wide range of applications including biosensing, bioimaging, tumour/infection therapy, bone regeneration and wound repair. By applying bioactive materials to modify the surface of MXenes, a series of multifunctional MXene-based nanomaterials can be designed for different biomedical applications to achieve better therapeutic effects or more desirable biological functions. This paper reviews the existing studies on MXene-based bioactivities, surface modification strategies and biomedical applications. Finally, the challenges, trends and prospects of MXene nanomaterials are discussed. We expect that more and more well-designed MXene-based biomaterials will have a wider range of biomedical applications, thus providing favourable information for the clinical translation of nanomedicine.

Skin wound healing is a complex process requiring coordinated cellular and molecular interactions. Polynucleotides (PN) and hyaluronic acid (HA) have emerged as promising agents in regenerative medicine due to their ability to enhance cellular proliferation, angiogenesis, and extracellular matrix (ECM) remodeling. Combining PN and HA offers potential synergistic effects, accelerating wound repair.

PN and HA hydrogels were prepared and evaluated for viscosity and gel stability. Their effects on human dermal fibroblasts (HDF) and keratinocytes (HaCaT) were assessed using migration, proliferation assays, and gene expression analyses for vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and matrix metalloproteinase-10 (MMP-10). In vivo studies were conducted using a mouse wound model to observe wound closure and tissue regeneration over 14 days.

The PN-HA mixture demonstrated superior mechanical stability compared to individual components. In vitro, PN-HA significantly enhanced HDF and HaCaT migration, proliferation, and upregulated VEGF, MMP-9, and MMP-10 expression. In vivo, PN-HA treatment accelerated wound closure, improved dermal thickness, and enhanced ECM remodeling, as evidenced by histological analyses.

The PN-HA combination synergistically accelerates wound healing by promoting angiogenesis, cellular migration, and ECM remodeling. These findings highlight its potential as an advanced wound dressing for acute and chronic wound management.

The skin acts as a crucial barrier and, upon injury, initiates complex wound-healing processes involving various cell types. Polydeoxyribonucleotides (PDRNs) are well-known for their efficacy in enhancing skin regeneration and wound healing. This study sought to investigate the effectiveness of PDRNs derived from Chlorella protothecoides, a sustainable and scalable microalgal source, in promoting skin regeneration and wound healing. Keratinocytes and fibroblasts were used for assessing the impact of PDRNs on cell proliferation, migration, collagen synthesis, and angiogenesis. Gene expression and associated signaling pathways were also examined using RT-qPCR and Western blot analyses. Our findings demonstrated that PDRNs significantly enhanced the proliferation and migration of skin cells, upregulated growth arrest specific 6 (GAS6) and hepatocyte growth factor (HGF) expression, and increased collagen synthesis by modulating collagen type I alpha 1 (COLIA1) expression. Additionally, PDRNs enhanced angiogenesis by promoting vascular endothelial growth factor (VEGF) expression and activation of ERK, AKT, β-catenin and STAT3 pathways via an adenosine A2A receptor (A2AR)-dependent mechanism. These findings suggest that microalgal-derived PDRNs have significant potential as sustainable and effective agents for clinical and cosmetic applications aimed at improving skin health and wound healing.