Angiogenesis is a complex physiological process. In recent years, the immune regulation of angiogenesis has received increasing attention, and innate immune cells, which are centred on macrophages, are thought to play important roles in vascular neogenesis and development. Various innate immune cells can act on the vasculature through a variety of mechanisms, with commonalities as well as differences and synergistic effects, which are crucial for the progression of vascular lesions. In recent years, monotherapy with antiangiogenic drugs has encountered therapeutic bottlenecks because of the short-term effect of 'vascular normalization'. The combination treatment of antiangiogenic therapy and immunotherapy breaks the traditional treatment pattern. While it has a remarkable curative effect and survival benefits, it also faces many challenges. This review focuses on innate immune cells and mainly introduces the regulatory mechanisms of monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs) and neutrophils in vascular lesions. The purpose of this paper was to elucidate the underlying mechanisms of angiogenesis and development and the current research status of innate immune cells in regulating vascular lesions in different states. This review provides a theoretical basis for addressing aberrant angiogenesis in disease processes or finding new antiangiogenic immune targets in inflammation and tumor.

Bioadhesives have found significant use in medicine and engineering, particularly for wound care, tissue engineering, and surgical applications. Compared to traditional wound closure methods such as sutures and staples, bioadhesives offer advantages, including reduced tissue damage, enhanced healing, and ease of implementation. Recent progress highlights the synergy of bioadhesives and immunoengineering strategies, leading to immunomodulatory bioadhesives capable of modulating immune responses at local sites where bioadhesives are applied. They foster favorable therapeutic outcomes such as reduced inflammation in wounds and implants or enhanced local immune responses to improve cancer therapy efficacy. The dual functionalities of bioadhesion and immunomodulation benefit wound management, tissue regeneration, implantable medical devices, and post-surgical cancer management. This review delves into the interplay between bioadhesion and immunomodulation, highlighting the mechanobiological coupling involved. Key areas of focus include the modulation of immune responses through chemical and physical strategies, as well as the application of these bioadhesives in wound healing and cancer treatment. Discussed are remaining challenges such as achieving long-term stability and effectiveness, necessitating further research to fully harness the clinical potential of immunomodulatory bioadhesives.

Developing hydrogel dressings with the capabilities to accommodate irregular wounds and provide a cascade disinfective-regenerative microenvironment for wound repair is of great importance to combating pathogenic bacteria-infected wounds but remains an ongoing challenge. To address the conundrum, we devise a molybdoenzymes-emulating bio-heterojunction (M-bioHJ) doped double network (DN) hydrogel dressing for bacterial-infected wound healing. The near-infrared (NIR) photothermal effect of the M-bioHJ facilitates the exchange of multiple dynamic crosslinking sites in the hydrogel, endowing the hydrogel with photo-remote reprocessing capabilities to completely accommodate the encountered irregular wounds and ultimately accomplish the admirable therapeutic effect. Meanwhile, the introduced M-bioHJ shows NIR light-enhanced photodynamic activity to induce a massive engendering of reactive oxygen species (ROS), allowing rapid sterilization without reliance on exogenous hydrogen peroxide. Furthermore, the Mo ions released from the M-bioHJ-encapsulated hydrogel can play a crucial role in reprogramming the macrophage phenotype and determining tissue regeneration. Both in vitro and in vivo evidences authenticate the accelerated healing potential of infected wounds through the synergistic effects of photo-reprocessing, disinfection, and macrophage-reprogramming facilitated by the hydrogel. These findings highlight the promising application prospects of such neoteric M-bioHJ-encapsulated hydrogel dressings for wound disinfection and tissue regeneration.

Wound management plays a crucial role in nursing care as it facilitates effective wound healing and prevents infections. To overcome limitations associated with traditional treatment methods, various smart bandages have been developed. The monitoring of wound parameters and the implementation of targeted treatments are crucial aspects of smart bandage development. Smart bandages, as cutting-edge flexible wearable medical devices, integrate various sensing technologies, providing new insights for dynamic monitoring and personalized treatment of chronic wounds. This paper systematically summarizes the applications and developments of smart bandages in monitoring wound environmental parameters, focusing on two major detection methods: colorimetric sensing and electrochemical sensing. Colorimetric sensors typically rely on color changes induced by physiological parameters, which can not only be identified by the naked eye but also combined with image recognition algorithms for physiological parameter detection. Electrochemical sensors, on the other hand, modify electrodes with specific enzymes and detect physiological parameters through the electrical signals generated by redox reactions. In addition to sensing, this paper further explores the integrated application of three smart therapeutic strategies in smart bandages, including promoting cell proliferation and angiogenesis through electrical stimulation, achieving controlled drug release via responsive materials, and utilizing photothermal materials for efficient antibacterial treatment of wounds. Finally, the paper delves into the challenges these bandages face in system integration and clinical translation, and discusses their potential in personalized wound care.

Chronic wounds are difficult to heal due to pathogenic microbial colonization and dysregulation of healing cascades, necessitating novel therapeutic strategies. This study developed a multifunctional nanosystem by integrating the antimicrobial peptide LL37 with cationic polyaminoglycoside (SS-HPT), constructing a self-sustaining "AMP factory" to achieve multi-stage modulation of the wound healing. Validation through cell-level experiments and in vivo dual models (mechanical injury and bacterial infection) in immunocompromised rats demonstrated the system's unique dual intracellular-extracellular pathogen-killing capability, significantly accelerating the wound healing process. Transcriptomic analysis revealed that its mechanism involves the dual effects of suppressing pro-inflammatory factor expression and activating tissue repair pathways. Histological evidence confirmed that the system promotes angiogenesis, enhances re-epithelialization rates, and guides orderly collagen fiber deposition. This nanosystem, combining efficient AMP delivery and integrated therapeutic strategies, achieves three-dimensional synergy in microbial clearance, immune microenvironment regulation, and tissue matrix remodeling, providing theoretical and technical foundations for a paradigm shift in chronic wound treatment.

Women's health management plays a crucial role in modern healthcare, encompassing the prevention, detection, and treatment of female diseases. However, existing technologies often face challenges, such as the invasiveness and discomfort associated with serological testing and injection-based therapies. Microneedles, as an emerging technology in biomedical engineering, demonstrate significant advantages. These micron-sized transdermal devices are applicable in a range of applications, from drug delivery to interstitial fluid sampling, and their painless, minimally invasive nature significantly enhances medication compliance. In recent years, microneedles have been widely utilized in women's health management, showing promising results in early disease prevention and subsequent treatment. Although there are reviews about microneedles applied in disease treatment management, few of them focus on the application of microneedles in the prevention and early detection of women's disease. Herein, we present a comprehensive overview of the current application status of microneedles in women's health management, with a special emphasis on their design and mechanism for disease prevention, and treatment in women. Finally, we discuss the advantages and limitations of microneedles in women's health management, and propose suggestions for future research direction.

Functional hydrogel dressings offer a promising therapeutic approach, and optimizing their formulations is crucial for improving diabetic foot ulcers (DFUs) outcomes. This study explores the comparative efficacy of different functional hydrogel dressings in DFUs treatment.

We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating functional hydrogel dressings for DFUs treatment. A comprehensive search was performed across PubMed, Embase, CENTRAL, CNKI and Web of Science from inception to June 2024. Bayesian network meta-analysis was employed to synthesize and compare the relative efficacy of hydrogel interventions, defined as the number of patients with complete wound closure.

In total, 23 studies involving 1671 patients with DFUs were included. The analysis revealed that immuno-regulating hydrogels (IRHs) had the highest effect estimate (2.2, 95% CI: 1.6, 3.2), compared with anti-bacterial hydrogels (ABHs) ranked last (1.3, 95% CI: 0.78, 2.3). Multi-functional hydrogels (MFHs) and proliferation-promoting hydrogels (PPHs) displayed intermediate effects (1.7, 95% CI: 1.2, 2.4). The relative efficacy ranking was IRH > MFH/PPH > ABH > placebo. The risk of adverse events was lower in functional hydrogel groups relative to placebo (0.75, 95% CI: 0.56, 0.96). Node-splitting analysis confirmed the consistency between direct and indirect evidence for IRH versus ABH. A funnel plot analysis indicated no significant publication bias, affirming the robustness of our findings.

This study provides a comprehensive evaluation of functional hydrogel dressings for DFUs treatment, highlighting the potential of IRH as the most effective option. These insights will guide future research and clinical applications to improve DFUs management.

Acute wounds present a significant clinical challenge due to delayed healing, which is often exacerbated by elevated levels of reactive oxygen species (ROS). These high ROS concentrations hinder the natural healing process, leading to prolonged recovery and increased risk of complications. W-GA nanodots, synthesized via a simple coordination method, have emerged as promising solutions, demonstrating multifunctional enzymatic activity that effectively scavenges ROS. To explore the underlying mechanisms of ROS-induced oxidative stress, we conducted RNA sequencing on macrophages exposed to H2O2. The results revealed significant regulation of key stress response pathways, including substantial upregulation of the "p53 signaling pathway" and the "HIF-1 signaling pathway," both of which are essential for cellular adaptation to oxidative stress. By alleviating oxidative stress, W-GA nanodots not only accelerate wound repair but also improve overall healing outcomes. Notably, RNA sequencing of animal tissue samples revealed that W-GA nanodots activate the "Wnt signaling pathway," further promoting wound healing. These findings underscore the potential of W-GA nanodots as a novel therapeutic strategy for enhancing wound healing and treating oxidative stress-related conditions, positioning them as promising candidates for future clinical applications in wound care and inflammatory diseases.

Persistent inflammation is a major cause of diabetic wounds that are difficult to heal. This is manifested in diabetic wounds with excessive reactive oxygen clusters (ROS), advanced glycation end products (AGE) and other inflammatory factors, and difficulty in polarizing macrophages toward inhibiting inflammation. Berberine is a natural plant molecule that inhibits inflammation; however, its low solubility limits its biological function through cytosis. In this study, we designed F127 micelles to encapsulate berberine with the aim of improving its solubility and bioavailability. Meanwhile, in order to achieve effective drug delivery at the wound site, we designed an injectable ferrocene-cyclodextrin self-assembled oxidation-reactive supramolecular hydrogel drug delivery system. Cellular experiments have shown that the hydrogel can reduce intracellular ROS and AGE production, attenuate cellular damage, promote macrophage polarization toward inhibition of inflammation, and reduce the secretion of inflammatory factors. In an animal model of diabetic mice, this hydrogel dressing reduces the level of inflammation in diabetic wounds, optimizes collagen deposition in diabetic wounds, and ultimately achieves high-quality diabetic wound healing. The work offers a straightforward and effective solution to the challenge of administering hydrophobic anti-inflammatory agents in the context of diabetic wound therapy.

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.

Although the antibacterial properties of glycine-rich peptides from prokaryotes to eukaryotes have been well characterized, their role in skin wound healing remains poorly understood, especially non-bactericidal glycine-rich peptides. Herein, a novel glycine-rich (46.5%) peptide (Smaragin, SRGSRGGRGGRGGGGRGGRGRSGSGSSIAGGGSRGSRGGSQYA) was identified from the skin of the tree frog Zhangixalus smaragdinus. Unlike other glycine-rich peptides, Smaragin showed no antimicrobial activity in vitro but significantly enhance wound healing in full-thickness dermal wounds in mice. In comparison with other wound healing-promoting peptides, Smaragin did not directly affect the proliferation and migration of keratinocytes, vascular endothelial cells, and fibroblasts. However, it notably increased phagocytes infiltration at the wound site by 0.5-day post-injury. Smaragin was not a direct chemoattractant for phagocytes, but it stimulated macrophages to secrete chemokines CXCL1 and CXCL2, which indirectly enhanced the migration of phagocytes, keratinocytes and vascular endothelial cells. Moreover, Smaragin promoted the polarization of macrophages from a pro-inflammatory M1-type to an anti-inflammatory M2 phenotype at the wound, which is associated with angiogenic activity. As expected, CD31, the most common analyzed marker of angiogenesis, showed a significant increase in vascular network area. Subsequent studies revealed that Smaragin promoted the chemokine level and polarization of macrophages via the TLR4/MAPK/NF-κB pathway, which enhanced the number of phagocytes and the regeneration of the epidermis and blood vessels at the wound, thereby accelerating skin wound healing in mice. These findings highlight the skin healing properties of non-bactericidal glycine-rich peptides and display the potential of Smaragin as a promising candidate for developing effective wound healing therapies.

Persistent excessive inflammatory response in diabetic wounds caused by the imbalance of the immune microenvironment leads to delayed or nonhealing of the wounds. Timely attenuation of inflammation through immunoregulation is a crucial strategy to accelerate diabetic wound closure. Here, the protocatechuic acid (PCA)- and deferoxamine (DFO)-loaded polysaccharide-based immunoregulatory hydrogel (POCP@D) was developed by the dual-cross-linking strategy of borate ester bonds and imine bonds to promote advanced healing of full-thickness diabetic wounds. The POCP@D hydrogel showed good tissue adhesiveness property, flexibility, mechanical strength, injectability, self-healing, and glucose-responsive drug release properties, besides strong broad-spectrum antibacterial and antioxidant activities. The POCP@D hydrogel acted as an immunoregulatory platform to remold the in vivo immune microenvironment of diabetic wounds by regulating the M2-type macrophage polarization and timely relieving wound inflammation, thus promoting collagen deposition, angiogenesis, and the development of diabetic wounds from the inflammatory stage to the proliferative stage and ultimately achieving high-quality skin tissue regeneration. Overall, our developed immunoregulatory hydrogel held great potential for refractory diabetic wound therapy in clinical settings.

The prevalence of gestational diabetes mellitus (GDM) is currently on the rise globally, which heightens the risk of adverse pregnancy outcomes and subsequently increases the likelihood of cesarean delivery. GDM can induce hyperglycemic conditions in cesarean wounds, leading to delayed wound healing and complications such as itching, pain, and scarring. These complications significantly impact the quality of life and mental health of mothers. Furthermore, there is a lack of effective clinical prevention strategies. Consequently, the need to improve wound healing after cesarean sections in women with GDM is a pressing concern that warrants our attention. To maximize the therapeutic impact and extend the bioavailability of calycosin-7-glucoside (CG), it was integrated into a hybridized hydrogel (GOHA) as a drug carrier to create the GOHACG hydrogel. Bases on our tests, the GOHACG hydrogel demonstrated a strong capacity for water absorption, appropriate pore size, and good biocompatibility to adjust to the in situ surroundings of the wound. GOHACG also promoted epidermal regeneration, collagen deposition, angiogenesis, and the conversion of macrophages from the M1 to M2 phenotype. Indicating a reduction in the inflammatory response, accelerated wound repair, and minimized skin scarring in a postcesarean delivery model involving gestational diabetic mellitus mice. In brief, the GOHACG possesses significant properties that enhance wound healing in GDM model, suggesting its potential effects in treating wound healing of GDM.

Fibromodulin, a small leucine rich proteoglycan has been suggested to have prominent role in wound healing. On the other hand, fibroblast cells, due to their ability to secrete growth factors and control inflammation in the wound area, have been proposed as effective approaches in cell therapy for wounds. In the current study we attempted to improve treatment results using a combination of fibroblast and fibromodulin features.

Fibroblast cells were isolated from the skin and transfected with a vector carrying the fibromodulin gene. Following the assessment of fibromodulin protein production, the effect of transfected fibroblast cells was studied in an animal wound model.

Flow cytometry analysis showed high expression of the CD90 marker (97.2%) and very low expression of the CD34 marker (0.47%). Additionally, enzyme-linked immunosorbent assay (ELISA) findings confirmed high expression of the fibromodulin gene in the transfected fibroblast cells. In vivo studies demonstrated that the animals treated with fibroblast cells transfected with fibromodulin (V + G+) exhibited significantly improved wound contraction on day 7 (i.e., contraction percentage: 21.79 ± 9.96%, compared with 7.23 ± 2.30% in the PBS-treated group). Histopathological studies also indicated improvements in angiogenesis score and collagen density score in the animals treated with the V + G + group.

The results of this study showed that fibroblast cells expressing the fibromodulin gene improve wound contraction and some histological parameters in the deep wound model of the rat.

Treatment of chronic or non-healing wounds has faced a considerable clinical challenge and impose several detrimental effects on individuals, society, the healthcare system, and the economy. Bioactive peptides have been employed to accelerate wound healing in active wound treatment efficiently and effectively. In the current study, a novel wound-healing peptide, WHP1, was designed from 23 existing wound-healing peptides by a rational template-assisted approach. It demonstrated the ability to enhance migration and proliferation of human keratinocyte cell lines (HaCaT) without exhibiting cytotoxic effects on human red blood cells and HaCaT cells. By quantitative proteomic analysis, WHP1 exerted a multifaceted role on diverse cellular processes in human keratinocyte. Notably, it increased the expression of intracellular proteins of HaCaT cells involved in cell cycle regulation and focal adhesion, including centromeric histone H3 variant CENPA, ubiquitin-conjugating enzyme E2 C, thyroid receptor-interacting protein 6, and ribosomal components essential for cell adhesion and migration. WHP1 upregulated the key enzyme glyceraldehyde-3-phosphate dehydrogenase, orchestrating metabolic biosynthesis particularly glycolysis, cell cycle regulation, and cytoskeletal processes. An intriguing observation was the antioxidant activity of WHP1, protecting cells from reactive oxygen species-induced senescence. This is consistent with the upregulation of GAPDH expression and reduction of histone H2A.J levels. WHP1 also stimulated macrophages to secrete transforming growth factor-β (TGF-β), a crucial growth factor necessary for the remodeling phase of wound healing. This investigation highlighted the feasibility of rational design to create novel wound-healing peptides. Such advancements hold promise for improving patients' quality of life and elevating the standard of care in contemporary healthcare.

Keratinocytes, the most important cell type constituting the epidermis, migrate to restore the epithelial barrier during wound healing and are a crucial step in wound healing. This study utilized bioinformatics analysis of comprehensive expression datasets of aberrantly expressed genes in wound healing to identify the abnormal expression of the critical transcription factor Fos-like antigen-1 (FOSL1), which is involved in various diseases. Currently, there is limited research on the role of FOSL1 in wound healing, and its molecular mechanisms remain unclear. This study explores the role and regulatory mechanisms of FOSL1 in the wound-healing process. A comprehensive expression dataset of abnormal genes in wound repair was constructed by bioinformatics analysis. Mouse trauma models and mouse wound splint models were constructed to verify the role of FOSL1 in vivo. Real-time quantitative polymerase chain reaction (qRT-PCR), immunoblot, immunofluorescence staining, and HE staining were used to confirm the analysis, and FOSL1 was used as the target in the wound healing process. At the cellular level, using 5'-ethynyl-2'-deoxyuridine (EdU) assay, Transwell assay, Migration assay, western blotting and immunofluorescence, FOSL1 promoted the molecular mechanism of wound repair by regulating the proliferation and migration of keratinocytes through IL-17 signaling pathway. Bioinformatics analysis revealed differential expression of FOSL1 during wound healing. In the mouse back wound model, qRT-PCR, western blotting (WB), and immunofluorescence staining showed significant upregulation of FOSL1 and IL-17 expression during wound tissue healing, indicating a close association between FOSL1 and mouse wound healing. In the mouse wound splinting model, subcutaneous injection of recombinant FOSL1 protein contributed to wound surface healing. Overexpression of FOSL1 in HaCaT cells promoted their proliferation and migration abilities. When IL-17 inhibitor was added to HaCaT cells, both FOSL1 overexpression and knockdown inhibited the proliferation and migration abilities of HaCaT cells. Thus, this study confirms that FOSL1 promotes keratinocyte proliferation and migration through the IL-17 signaling pathway, facilitating wound healing in epidermal wound repair. The results of this study indicate that FOSL1 plays a key role in epidermal wound healing, and elucidate a new molecular mechanism by which FOSL1 promotes keratinocyte proliferation and migration through IL-17 signaling pathway in epidermal wound repair, thereby promoting wound healing.

Wound healing is a complex biological process and remains a significant challenge due to the lack of effective therapeutic drugs. Cayratia japonica (CJG), a traditional folk medicine, has been widely used for its anti-inflammatory and efficacy in treating traumatic injuries.

This study aimed to investigate the wound-healing effects of CJG and elucidate its underlying mechanism.

First, the phytochemical composition of CJG was identified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and its potential wound-healing mechanisms were predicated via network pharmacology. Next, in vivo experiments were conducted by dividing subjects into control, CJG (1.5-6 mg/cm2), and bFGF (150 IU/cm2) groups to assess its therapeutic efficacy. Finally, the mechanism of CJG and its key bioactive component, luteolin-7-O-glucoside (LUT-7G), were explained through polymerase chain reaction (PCR), Western blotting, histopathology, immunofluorescence, plasmid transfection, colony formation unit assays, and cellular thermal shift assay (CETSA).

LC-MS/MS identified 15 major constituents of CJG and 102 potential wound healing-related targets. Network pharmacology analysis revealed key enriched pathways, including AMPK, TNF, and metabolic pathways. In vivo, CJG significantly accelerated wound-healing by inhibiting inflammatory responses, promoting angiogenesis, and modulating collagen deposition. In vitro, LUT-7G treatment markedly enhanced the proliferation and migration of HaCaT and HSF cells. Mechanistically, LUT-7G exerted its wound-healing effects by activating the AMPK/CTHRC1/TGF-β1 signaling pathway in HaCaT cells. In conclusion, CJG significantly promotes wound healing by regulating AMPK signaling pathways, indicating its promising clinical application prospects.

Despite advancements in molecular science and biomaterial technology, the mechanisms underlying the impaired healing of diabetic wounds remain unclear. In this study, we investigated the post-transcriptional regulation of diabetic wound healing using JAM-A.

Mouse wound models, hematoxylin and eosin staining analysis, and scratch wound assays were used to investigate the effects of JAM-A 3'-UTR on the re-epithelialization of diabetic wounds, whereas RNA pulldown, microRNA-seq, and bioinformatics analyses were performed to identify key miRNA players and predict their target genes. In situ hybridization, immunohistochemistry, western blotting, and polymerase chain reaction (PCR) were used to confirm the alternative splicing of JAM-A 3'-UTR in diabetic conditions. CCK-8 proliferation assays, scratch wound assays, PCR, western blotting, and dual-luciferase assays were performed to study the changes in cell proliferation and migration induced by miR-106b-5p modification and confirm the target gene.

JAM-A 3'-UTR accelerated re-epithelialization in diabetic mouse wounds. Shortened splicing was found in the 3'-UTR of JAM-A under diabetic conditions, leading to the excessive release of miR-106b-5p while the promoter of miR-106b was activated. Furthermore, upregulated miR-106b-5p over-activated cell proliferation and inhibited cell migration in diabetic wound keratinocytes by suppressing the target gene PTEN/TIAM1 and regulating the AKT and RAC1 pathways, thereby impairing wound re-epithelialization.

We identified alternative splicing of JAM-A 3'-UTR in diabetic conditions, which caused the excessive release of miR-106b. Upregulation of miR-106b reduced the expression of its target genes, PTEN and TIAM1, which led to hyperactive proliferation and impaired migration of keratinocytes, thereby dysregulating wound re-epithelialization.

Chronic wounds present significant clinical challenges due to delayed healing and high infection risk. This study presents the development and characterisation of acrylated hyaluronic acid (AcHyA) hydrogels functionalised with gelatin (G) and the antimicrobial peptide (AMP) PP4-3.1 to enhance cellular responses while providing antimicrobial activity. AcHyA-G and AcHyA-AMP hydrogels were formed via thiol-acrylate crosslinking, enabling in situ AcHyA hydrogel formation with stable mechanical properties across varying gelatin concentrations. Biophysical characterisation of AcHyA-G hydrogels showed rapid gelation, elastic behaviour, uniform mesh size, and consistent molecular diffusion across all formulations. Moreover, the presence of gelatin enhanced stability without affecting the hydrogel's degradation kinetics. AcHyA-G hydrogels supported the adhesion and spreading of key cell types involved in wound repair (dermal fibroblasts and endothelial cells), with 0.5% gelatin identified as the optimal effective concentration. Furthermore, the conjugation of the AMP conferred bactericidal activity against Staphylococcus aureus and Escherichia coli, two of the most prevalent bacterial species found in chronically infected wounds. These results highlight the dual function of AcHyA-AMP hydrogels in promoting cellular responses and antimicrobial activity, offering a promising strategy for chronic wound treatment. Further in vivo studies are needed to evaluate their efficacy, including in diabetic foot ulcers.

Infected wounds present a significant clinical challenge, exacerbated by antibiotic resistance, which complicates effective treatment. This study introduces a hydrogel (CC/AP@CM) embedded with core-shell bioactive glass nanoparticles designed for the controlled, sequential release of copper (Cu2+) and magnesium (Mg2+) ions. The hydrogel is crosslinked via a Schiff base reaction, endowing it with injectable, self-healing, and adhesive properties. Notably, the bilayer structure of the bioactive glass within the hydrogel allows an initial release of Cu2+ ions to trigger an early-stage pro-inflammatory and antimicrobial response, followed by Mg2+ ions that support tissue repair and an anti-inflammatory environment. This design aligns with natural wound healing stages, promoting a shift in macrophage polarization from the M1 to M2 phenotype, effectively balancing antibacterial defense with tissue regeneration. The hydrogel demonstrated robust antibacterial efficacy against MRSA, increased angiogenesis, and enhanced fibroblast proliferation and migration in vitro. In a murine wound model, it significantly accelerated wound closure and immune activation, including responses from dendritic cells and T cells. These findings suggest that this hydrogel, through its stage-specific immunomodulatory properties and temporally controlled ion release, offers a promising strategy for treating complex wound infections, supporting both immune defense and tissue healing.

Delayed diabetic wound regeneration can be attributed to multiple underlying factors, including bacterial infection, endogenous reactive oxygen species (ROS), impaired angiogenesis and exaggerated inflammatory response. Here, a bilayer electrospun nanofibrous membrane (ENM) was fabricated through sequential electrospinning to accelerate diabetic wound healing by addressing aforementioned challenges. For the purpose, nano Zinc Oxide was mixed into chitosan as the bottom layer of ENM (CS/ZnO NPs), while astaxanthin (AST) was encapsulated in a composite nanofibrous membrane of polyvinyl alcohol, chitosan and Ti3C2TX MXene (PVA/CS/MXene) as the upper layer, thus preparing the bilayer CZ/PCM@AST ENM, which reflected the therapeutic properties of spatial structure distribution and time series on diabetic wounds. The bilayer CZ/PCM@AST ENM was verified to possess sufficient biocompatibility and effective antibacterial properties on E. coli and S. aureus. Furthermore, the ENM facilitated sustained AST release at inflammatory sites, effectively scavenging excessive ROS and inhibiting inflammatory responses, ultimately accelerating diabetic wound healing, as demonstrated through both in vitro and in vivo evaluations. In summary, the multi-effect combination strategy improved complicated pathological microenvironment of wound sites, thereby presenting a promising method in diabetic wound treatment.

Inflammation is the body's response to infection, trauma or injury and is activated in a coordinated fashion to ensure the restoration of tissue homeostasis and healthy physiology. This process requires communication between stromal cells resident to the tissue compartment and infiltrating immune cells which is dysregulated in disease. Clinical innovations in patient diagnosis and stratification include measures of inflammatory activation that support the assessment of patient prognosis and response to therapy. We propose that (i) the recent advances in fast, dynamic monitoring of inflammatory markers (e.g., cytokines) and (ii) data-dependent theoretical and computational modeling of inflammatory marker dynamics will enable the quantification of the inflammatory response, identification of optimal, disease-specific biomarkers and the design of personalized interventions to improve patient outcomes - multidisciplinary efforts in which biomedical engineers may potentially contribute. To illustrate these ideas, we describe the actions of cytokines, acute phase proteins and hormones in the inflammatory response and discuss their role in local wounds, COVID-19, cancer, autoimmune diseases, neurodegenerative diseases and aging, with a central focus on cardiac surgery. We also discuss the challenges and opportunities involved in tracking and modulating inflammation in clinical settings.

Introduction: Hypertrophic and keloid scars are abnormal tissue growth that can be disfiguring, for which the available treatment has not yielded consistent results. Therefore, this study aimed to evaluate the capability of Adipose tissue-derived stem cell (ADSC) therapy in treating these scars. Methods: A literature search was conducted on PubMed, Scopus, Cochrane Library, and Web of Science from inception until July 2022. We included experimental studies that evaluated ADSCs as a therapy for hypertrophic and keloid scars in both in-vivo and in-vitro models. Results: Our findings extracted from 12 included studies demonstrated that ADSCs have a promising potential in reducing collagen deposition, proliferation, and migration rates of fibroblast, decreasing gene/protein expression of scar-related molecules including levels of TGF-β1 and lowering intracellular signal pathway-related molecules of hypertrophic and keloid scars in both models. However, no significant difference (P > .05) was found in the hypertrophic scar in-vitro models in terms of DCN gene expression. Conclusion: Ultimately, the current studies included in this systematic review support the use of ADSCs to alleviate hypertrophic and keloid scars.

The therapeutic efficacy of a nanomedicine or a natural biomaterial can vary in different disorders due to their complex pathophysiology. A nanomedicine that is capable of not only targeting specific pathological cues through functional ligands but also optimizing the therapeutic efficacy of its components throughout the intricate pathways involved in complex disorders is highly desired. Here, ceria-nanoparticle-entangled reticulation for angiogenic and therapeutic embrocation (CERATE), composed of hyaluronic acid, levofloxacin, and the as-synthesized ceria nanoparticles is developed. CERATE is formulated in situ as a rigid nanoparticle-based network that integrates its components intimately using highly diluted concentrations, thereby augmenting the therapeutic efficiency of its individual components. The physical states of CERATE can be altered freely while retaining its integrity, by adjusting the water proportion to accommodate diverse clinical needs. This physically robust CERATE can withstand enzymatical degradation, display antibacterial activity, scavenge reactive oxygen species, and improve the migration and proliferation of fibroblasts by activating the proangiogenic factors. CERATE accelerates the repair of diabetic wounds by promoting both the angiogenesis and the synthesis of collagen. The results demonstrate the effectiveness of a multifactorial approach involving the recruitment of minimally modified biofunctional ligands and nanomaterials altogether with synergistic efficacy in treating complex disorders.

Efficient wound healing remains a formidable medical challenge in clinical practice, due to the prevalence of skin defects arising from diverse etiological factors. It is indisputable that epidermal growth factor (EGF) plays a pivotal role in wound repair. However, its clinical application through recombinant proteins encounters challenges, including a short half-life in vivo and high production costs. Addressing these limitations, recent advancements in chemically modified mRNA (cmRNA) technologies offer a promising alternative. This study explores the utilisation of cmRNA in a biocompatible citrate-saline formulation to encode EGF for therapeutic purposes, capitalising on the advantages of cmRNA's inherent stability and the formulation's compatibility with biological systems. CmRNA demonstrated high transfection efficiency in human immortalised keratinocyte (HaCaT) and normal human dermal fibroblasts (NHDF) cells (93.97% ± 1.25% and 90.37% ± 0.97%, respectively), resulting in efficient production of biologically active EGF protein. In vitro, EGF cmRNA significantly promoted HaCaT and NHDF cell cycle, proliferation and migration. In vivo, in vivo imaging system (IVIS) imaging of murine skin confirmed localised and sustained expression of Luciferase cmRNA, with signals detectable up to 11 days post-injection. Immunohistochemistry revealed protein expression in both epidermal and dermal layers as early as 1 h post-injection, peaking at 48 h, further corroborated by enzyme-linked immunosorbent assay (ELISA). In a full-thickness skin defect mouse model, EGF cmRNA significantly accelerated wound healing, with superior re-epithelialisation observed compared to controls by Day 6. Mitogen-activated protein kinase (MEK)/Extracellular signal-regulated kinase (ERK) and Ki67 mRNA expression levels were markedly increased, both in vitro and in vivo. By Day 14, histological and immunohistochemical analyses revealed that EGF cmRNA outperformed recombinant human EGF (rhEGF), as indicated by enhanced formation of hair follicles and cutaneous glands, better-organised collagen fibres, and a reduced collagen Type I/III ratio. No adverse effects were observed in major organs, confirming cmRNA's biosafety. These results highlight the therapeutic potential of EGF-encoding cmRNA as an effective and safe alternative for enhancing wound healing.

The incidence and burden of skin wounds, especially chronic and complex wounds, have a profound impact on healthcare. Effective wound healing strategies require a multidisciplinary approach, and advances in materials science and bioengineering have paved the way for the development of novel wound healing dressing. In this context, electrospun nanofibers can mimic the architecture of the natural extracellular matrix and provide new opportunities for wound healing. Inspired by the bioelectric phenomena in the human body, electrospun nanofibrous scaffolds with electroactive characteristics are gaining widespread attention and gradually emerging. To this end, this review first summarizes the basic process of wound healing, the causes of chronic wounds, and the current status of clinical treatment, highlighting the urgency and importance of wound dressings. Then, the biological effects of electric fields, the preparation materials, and manufacturing techniques of electroactive electrospun nanofibrous (EEN) scaffolds are discussed. The latest progress of EEN scaffolds in enhancing skin wound healing is systematically reviewed, mainly including treatment and monitoring. Finally, the importance of EEN scaffold strategies to enhance wound healing is emphasized, and the challenges and prospects of EEN scaffolds are summarized.

Fibroblasts, once perceived as a uniform cell type, are now recognized as a mosaic of distinct populations with specialized roles in tissue homeostasis and pathology. Here we provide a global overview of the expanding compendium of fibroblast cell types and states, their diverse lineage origins and multifaceted functions across various human organs. By integrating insights from developmental biology, lineage tracing and single-cell technologies, we highlight the complex nature of fibroblasts. We delve into their origination from embryonic mesenchyme and tissue-resident populations, elucidating lineage-specific behaviours in response to physiological cues. Furthermore, we highlight the pivotal role of fibroblasts in orchestrating tissue repair, connective tissue remodelling and immune modulation across diverse pathologies. This knowledge is essential to develop novel fibroblast-targeted therapies to restore steady-state fibroblast function and advance regenerative medicine strategies across multiple diseases.

Pentachlorophenol (PCP) was extensively utilized as an organochlorine pesticide and wood preservative in the United States from the 1930s until the Environmental Protection Agency (EPA) imposed restrictions due to concerns about its toxicity and potential carcinogenic properties. Although it is no longer widely used, PCP remains a concern due to its environmental persistence and potential for long-term health effects. Significant occupational and environmental exposures have likely occurred, with the health and economic costs of PCP exposure potentially being substantial given its known toxicity. Notably, PCP exhibits rapid absorption through both the skin and respiratory system and has been shown to cause hepatotoxicity, developmental toxicity, immunotoxicity, irritation, and carcinogenicity in laboratory animal studies. PCP exposure induces oxidative stress, a key mechanism underlying its inflammatory and toxic effects, which can activate cellular stress responses including upregulation of heat shock protein 70 (Hsp70). Previous studies in lung and liver epithelial cells have shown that Hsp70 and oxidative stress play pivotal roles in triggering autophagy. This study establishes the critical role of the Hsp70-reactive oxygen species (ROS)-autophagy axis in regulating cellular responses to PCP exposure in human alveolar (A549) and liver carcinoma (HepG2) epithelial cells. Our research elucidated the molecular mechanisms underlying PCP's cellular effects, demonstrating that its exposure resulted in increased expression of autophagy-related proteins (Beclin-1, LC3B, ATG12, and ATG16), subunits of NADPH oxidase (NCF-1, NCF-2, NOX2, and Rac), and antioxidant proteins (SOD and GPx) in both lung and liver cell types. Notably, PCP augmented the interaction between Hsp70 and the autophagy regulator Beclin-1. Pretreatment with the ROS inhibitor N-acetylcysteine or Hsp70 knockdown markedly reversed PCP-induced responses. Our in-silico protein-protein docking analysis and molecular dynamics simulation studies revealed enhanced interactions and/or stable confirmations maintained throughout the simulations for TLR4-Hsp70 and Hsp70-Beclin-1 complexes in the presence of PCP. These findings provide a strong foundation for future studies, employing in vivo experimental models and human populations to identify promising targets for PCP-induced toxicity and cellular injury. Furthermore, these findings may have far-reaching implications for public health and environmental policy, ultimately leading to the identification of biomarkers and the development of more effective interventions for environmentally induced toxicity and diseases.

Tissue repair represents a highly intricate and ordered dynamic process, critically reliant on the orchestration of immune cells. Among these, neutrophils, the most abundant leukocytes in the body, emerge as the initial immune responders at injury sites. Traditionally recognized for their antimicrobial functions in innate immunity, neutrophils now garner attention for their indispensable roles in tissue repair. This review delves into their novel functions during the early stages of tissue injury. We elucidate the mechanisms underlying neutrophil recruitment and activation following tissue damage and explore their contributions to vascular network formation. Furthermore, we investigate the pivotal role of neutrophils during the initial phase of repair across different tissue types. Of particular interest is the investigation into how the fate of neutrophils influences overall tissue healing outcomes. By shedding light on these emerging aspects of neutrophil function in tissue repair, this review aims to pave the way for novel strategies and approaches in future organ defect repair, regeneration studies, and advancements in tissue engineering. The insights provided here have the potential to significantly impact the field of tissue repair and regeneration.

The skin, being the largest external organ, is highly vulnerable to injuries. To address the donor skin scarcity, tissue engineering and regenerative medicine have emerged as an alternative strategies to skin grafting over the past few decades. Recent advancements in 3D bioprinting technology however, have positioned it as a promising tool for constructing tissue that closely mimics in-vivo conditions, using a variety of biomaterials to meet the demands of tissue repair. An ideal 3D-printed tissue construct has the potential to provide an ideal tissue microenvironment, promoting wound healing while minimizing scar formation. In this study, we first optimized the bioink formulation by conducting toxicological evaluations, including skin irritation and skin sensitization tests, on two formulations of alginate-gelatin-DEAE cellulose, with and without fibrinogen. The addition of fibrinogen was found to reduce inflammation, making the fibrinogen-containing formulation the preferred choice for further studies. Further, we have analyzed the wound healing efficiency of 3D-printed dermal and epidermal-dermal constructs in rat full thickness wound model. Skin cells were isolated from rat tissue, and dermal, epidermal skin constructs were printed layer by layer using an alginate-gelatin-DEAE cellulose and fibrinogen-based bioink formulation, previously optimized in our laboratory. Full thickness excision wound was created and acellular, dermal and epidermal-dermal construct were implanted. Wound healing was analyzed by means of wound contraction, collagen synthesis, histopathological evaluation and gene expression analysis. Our results indicate that the epidermal-dermal construct promotes faster wound healing and enhanced angiogenesis compared to the dermal-alone and acellular constructs.

Aging is a gradual and irreversible process accompanied by the decline in tissue function and a significantly increased risk of various aging-related and geriatric diseases. Especially in the paradoxical context of accelerated global aging and the widespread emergence of pandemics, aging-related and geriatric diseases have become leading causes of individual mortality and disability, drawing increasing attention from researchers and investors alike. Despite the utility of current in vitro systems and in vivo animal models for studying aging, these approaches are limited by insurmountable inherent constraints. In response, microphysiological systems (MPS), leveraging advances in tissue engineering and microfluidics, have emerged as highly promising platforms. MPS are capable of replicating key features of the tissue microenvironment within microfabricated devices, offering biomimetic tissue culture conditions that enhance the in vitro simulation of intact or precise human body structure and function. This capability improves the predictability of clinical trial outcomes while reducing time and cost. In this review, we focus on recent advancements in MPS used to study age-related and geriatric diseases, with particular emphasis on the application of organoids and organ-on-a-chip technologies in understanding cardiovascular diseases, cerebrovascular diseases, neurodegenerative diseases, fibrotic diseases, locomotor and sensory degenerative disorders, and rare diseases. And we aim to provide readers with critical guidelines and an overview of examples for modeling age-related and geriatric diseases using MPS, exploring mechanisms, treatments, drug screening, and other subsequent applications, from a physiopathological perspective, emphasizing the characteristic of age-related and geriatric diseases and their established correlations with the aging process. We also discuss the limitations of current models and propose future directions for MPS in aging research, highlighting the potential of interdisciplinary approaches to address unresolved challenges in the field.

This research delves into the advancements in chronic skin wound treatment, with a particular focus on diabetic foot ulcers, utilizing hyaluronic acid (HA)-based hydrogels. Hyaluronic acid, an integral component of the skin's extracellular matrix, plays a crucial role in process such as inflammation, angiogenesis, and tissue regeneration. Due to their three-dimensional network structure, biocompatibility, hydrophilicity, and gas exchange capabilities, HA-based hydrogels are considered highly suitable for promoting wound healing. Nonetheless, pure HA hydrogels exhibit limitations including insufficient mechanical strength and rapid release of encapsulated substances. To address these limitations, the incorporation of bioactive materials such as chitosan and collagen was investigated. This combination not only optimized mechanical strength and degradation rates but also enhanced antibacterial and anti-inflammatory properties. Furthermore, responsive hydrogel dressings were developed to adapt to the specific characteristics of the diabetic wound microenvironment, enabling on-demand drug release. These advancements present new perspectives for the treatment of diabetic foot ulcers.

Wounds repairing after skin damage or diabetes remain a vast medical challenge, which often faces infection, inflammation, oxidative stress, and skin scarring. Herein, a multifunctional selenium-albumin nanoaccelerator hydrogel (H-Se NPs-Gel) is constructed based on the self-assembly of human serum albumin (HSA) with selenium nanoparticles (Se NPs) using carbomer as the carrier, it has remarkable antibacterial, anti-inflammatory, antioxidant and inhibits scarring properties than Se NPs for wound healing. Compared with Se NPs, H-Se NPs exhibit smaller particle sizes, exceptional stability, better antibacterial activity against common bacteria and MRSA, and superior antioxidant and anti-inflammatory capabilities in vitro without remarkable toxicity on skin cells. Importantly, it exhibits superior efficacy to Se NPs-Gel in accelerating the healing of full-thickness skin defects and diabetic wounds in mice. Interestingly, in a hypertrophic scar (HTS) model, H-Se NPs-Gel is more effective than Se NPs-Gel in inhibiting collagen formation to suppress scarring, which is mediated by the inhibition of CD36. The antagonistic effect of H-Se NPs on CD36 is also proved with the CD36 overexpression model. Furthermore, H-Se NPs-Gel demonstrates excellent safety in mice without systemic toxicity. H-Se NPs-Gel is an effective and safe therapy strategy for promoting wound healing and reducing scar formation in clinic.

Diabetic wounds present a significant healthcare challenge due to impaired healing mechanisms, with dermal fibroblasts playing a crucial role in tissue repair. This study investigates the role of transient receptor potential canonical-3 (TRPC3) in the dysfunction of diabetic fibroblasts and explores the therapeutic potential of TRPC3 inhibition. Findings reveal that TRPC3 expression is significantly elevated in diabetic dermal fibroblasts, which correlates with suppressed transforming growth factor-beta (TGF-β) signaling and impaired differentiation into myofibroblasts. Inhibiting TRPC3 effectively restores fibroblast functionality by upregulating TGF-β1 and its downstream effector, SMAD4. This restoration enhances the expression of key myofibroblast markers, such as α-smooth muscle actin (ACTA2) and type I collagen (COL1a1), which are essential for wound contraction and extracellular matrix remodeling. These results establish TRPC3 as a critical regulator of fibroblast activity and present TRPC3 inhibition as a promising therapeutic strategy for improving wound healing in diabetic patients.

Wound healing remains a significant challenge in clinical practice, driving ongoing exploration of innovative therapeutic approaches. In recent years, electrophysiological-based wound healing strategies have gained considerable attention. Specifically, electrical hydrogels combine the synergistic effects of electrical stimulation and hydrogel properties, offering a range of functional benefits for wound healing, including antibacterial activity, real-time wound monitoring, controlled drug release, and electrical treatment. Despite significant progress made in electrical hydrogel research for wound healing, there is a lack of comprehensive, systematic reviews summarizing this field. In this review, we survey the latest advancements in electrical hydrogel technology. After analyzing the mechanisms of electrical stimulation in promoting wound healing, we establish a novel classification framework for electrical hydrogels based on their operational principles. The review further provides an in-depth evaluation of the therapeutic efficacy of these hydrogels in various types of wounds. Finally, we propose future directions and challenges for the development of electrical hydrogels for wound healing.

Diabetes, both Type 1 and Type 2, often leads to chronic wounds due to impaired healing processes, marked by prolonged inflammation, delayed blood vessel formation, and abnormal collagen production. These issues disrupt normal tissue regeneration, slowing healing. To address these challenges, polymer-based wound dressings are being explored as a promising solution. Natural polymers like alginate, chitosan, and hyaluronic acid, as well as synthetic ones like PCL, PLA, and PLGA, offer potential for more effective healing. These materials can be used in advanced delivery systems, such as nanofibrous scaffolds, nanoparticles, and hydrogels, which help deliver medications, maintain a moist healing environment, and stimulate cell growth. By improving the wound environment, polymer-based systems provide new hope for diabetic patients with slow-to-heal wounds, enhancing therapeutic outcomes and accelerating healing. These innovations could significantly improve the management of chronic wounds in diabetes.

MicroRNAs (miRNAs) control organogenesis in mammals by inhibiting translation of mRNA. Skin is an excellent model to study the role of miRNAs in epidermis and the mesenchyme. Previous research demonstrated miRNA-29 family functions in skin; however, the mRNA targets and the downstream mechanisms of miRNA-29-mediated regulation are missing. We used the miRNA crosslinking and immunoprecipitation method to find direct targets of miRNA-29 in keratinocytes and fibroblasts from human skin. miRNA-29 inhibition using modified antisense oligonucleotides in 2D and 3D cultures of keratinocytes and fibroblasts enhanced cell-to-matrix adhesion through autocrine and paracrine mechanisms of miRNA-29-dependent tissue growth. We reveal a full transcriptome of human keratinocytes with enhanced adhesion to the matrix, which supports regeneration of the epidermis and is regulated by miRNA-29. Impact statement The functions of small, therapeutically targetable microRNA molecules identified in our study can provide a new approach to improve wound healing by restoring and enhancing the inner molecular mechanisms of a cell and its surrounding matrix. We also provide a plethora of new mRNA targets for follow-up studies of cell adhesion and extracellular matrix formation in humans.