One of the major problems faced with pre-implant bone reconstruction therapy is that large bone defects do not heal over time. Artificial bone graft materials, such as deproteinized bovine bone mineral, are commonly used in clinics. However, the lack of osteoinductive capacity and risk of post-implantation infections remain key limitations. Bioactive materials with strong bone formation and a high degree of biocompatibility are still needed. In this study, we synthesised bovine serum albumin nanoparticles (BNP) loaded with Tideglusib (TD), TD and BNP were bound together by self-assembly, and mixed with deproteinized bovine bone mineral (DBBM) to form a bone substitute material (TD-BNP@DBBM) that had low cytotoxicity, promoted cell proliferation and migration, induced cell differentiation, and regulated osteogenesis. In vitro, experiments suggested that TD-BNP@DBBM could promote osteoblast differentiation of MC3T3-E1 cells. In vivo, experiments demonstrated that TD-BNP@DBBM significantly accelerated bone reconstruction and enhanced bone healing in a rat cranial defect model. Furthermore, this result suggested a link between the Wnt/β-catenin pathway and the osteogenic effect, providing a basis for subsequent investigations into the mechanism of bone regeneration induced by osteogenic biomaterials. TD-BNP@DBBM might be a promising new approach for treating bone defects.

Intervertebral disc degeneration is a leading cause of lower back pain and is characterized by pathological processes such as nucleus pulposus cell apoptosis, extracellular matrix imbalance, and annulus fibrosus rupture. These pathological changes result in disc height loss and functional decline, potentially leading to disc herniation. This comprehensive review aimed to address the current challenges in intervertebral disc degeneration treatment by evaluating the regenerative potential of stem cell-based therapies, with a particular focus on emerging technologies such as exosomes and gene vector systems. Through mechanisms such as differentiation, paracrine effects, and immunomodulation, stem cells facilitate extracellular matrix repair and reduce nucleus pulposus cell apoptosis. Despite recent advancements, clinical applications are hindered by challenges such as hypoxic disc environments and immune rejection. By analyzing recent preclinical and clinical findings, this review provided insights into optimizing stem cell therapy to overcome these obstacles and highlighted future directions in the field.

In the field of large-area trauma flap transplantation, preventing avascular necrosis remains a critical challenge. Key mechanisms for improving flap viability include angiogenesis promotion, oxidative stress inhibition, and cell death prevention. Recently, two-dimensional ultrathin Ti3C2TX (MXene) nanosheets have gained attention for their potential contributions to these processes, though MXene's physiological impact on flap survival had not been previously investigated. This study is the first to confirm MXene's biological effects on the ischaemic microenvironment post-skin flap transplantation. Findings indicated that MXene significantly decreased the necrotic area in ischaemic flaps (37.96% ± 2.00%), with reductions of 30.40% ± 1.86% at 1 mg/mL and 20.19% ± 2.11% at 2 mg/mL in a concentration-dependent manner. Mechanistically, MXene facilitated in situ angiogenesis, mitigated oxidative stress, suppressed pro-inflammatory pyroptosis, and activated the PI3K-Akt pathway, particularly influencing vascular endothelial cells. Comparative transcriptome analysis of skin tissues with and without MXene treatment provided additional evidence, highlighting mechanisms such as pro-inflammatory pyroptosis, ROS metabolic processes, endothelial cell proliferation regulation, and PI3K-Akt signaling pathway activation. Overall, MXene demonstrated biological activity, effectively promoting ischaemic flaps survival and presenting a novel strategy for addressing ischaemic necrosis in skin flaps.

Cell membrane-derived nanovesicles (NVs) have emerged as promising alternatives to extracellular vesicles (EVs) for wound healing applications, addressing the limitations of traditional EVs, which include insufficient targeting capability, low production yield, and limited drug-loading capacity. Through mechanical cell extrusion methods, NVs exhibit superior characteristics, demonstrating enhanced yield, stability, and purity compared to natural EVs. These NVs can be derived from various membrane sources, including single cell types (stem cells, blood cells, immune cells, and bacterial membranes), hybrid cell membranes and cell membranes mixed with liposomes, with each offering unique therapeutic properties. The integration of genetic engineering and surface modifications has further enhanced NV functionality, enabling precise targeting and improved drug delivery capabilities. Recent advances in NV-based therapies have demonstrated their potential across multiple biomedical applications. Although challenges persist in terms of standardization, storage stability, and clinical translation, the combination of natural cell-derived functions with artificial modification potential positions NVs as a promising platform for next-generation therapeutic delivery systems, thereby offering new possibilities in wound healing applications. Finally, we explore the challenges and future prospects of translating NV-based therapeutics into clinical practice, providing insights into the future development of this innovative approach in wound healing and tissue repair.

To investigate the core targets and immunomodulatory mechanisms of Huoluo Xiaoling Pellet (HLXLP) for promoting tissue repair.

Network pharmacology and protein-protein interaction network were used to screen active components in HLXLP, the disease-related targets and the core targets, followed by GO and KEGG enrichment analyses and molecular docking to predict the pharmacological mechanisms. The toxicity of HLXLP was evaluated in zebrafish, and in a tissue regeneration model established in 3 dpf zebrafish larvae by amputating 95% of the tail fin, the effects of a formulated zebrafish embryo culture medium and 10, 20, and 40 μg/mL of aqueous extract of HLXLP on tissue regeneration was evaluated; RT-qPCR was performed to detect mRNA expressions of tissue regeneration marker genes and the core target genes. Transgenic zebrafish with fluorescently labeled macrophages and neutrophils were used to observe immune cell migration during tissue regeneration, and macrophage polarization at different stages was assessed with RT-qPCR.

We identified a total of 149 intersected targets between HLXLP active components and tissue repair and 5 core targets (AKT1, IL-6, TNF-α, EGFR and STAT3). GO and KEGG analyses suggested that the effects of HLXLP were mediated primarily through the JAK-STAT pathway, adhesion junctions and positive regulation of cell migration. HLXLP was minimally toxic below 40 μg/mL and lethal at 320 μg/mL in zebrafish, and caused renal and pericardial edema and vascular defects above 80 μg/mL. In zebrafish with tail fin amputation, HLXLP significantly promoted tissue regeneration, reduced IL-6 and TNF-α and enhanced AKT1, EGFR and STAT3 mRNA expressions, modulated neutrophil and macrophage recruitment to the injury sites, and regulated M1/M2 macrophage polarization during tissue regeneration.

HLXLP promotes zebrafish tail fin regeneration through multiple active components, targets and pathways for immunomodulation of immune cell migration and macrophage polarization to suppress inflammation and accelerate healing.

Crisaborole, as a phosphodiesterase 4 (PDE4) inhibitor (PDE4i), effectively inhibits inflammatory pathways, showing promising results in atopic dermatitis (AD), particularly in chronic hyperplasia lesions.

Based on real-world data from China, this study assesses the effectiveness and safety of 2% PDE4i ointment as monotherapy for chronic hyperplastic AD lesions.

A total of 49 AD patients aged 12 and above with chronic hyperplastic lesions and Investigator's Static Global Assessment scores of mild or moderate were enrolled. They received 2% PDE4i ointment twice daily until the lesions completely cleared. The effectiveness endpoints comprised the onset time of pruritus and lesion remission and the time of complete lesion clearance.

PDE4i demonstrated high effectiveness with minimal irritation, notable improvement in hyperpigmentation, and early remission of pruritus and lesions. The response varied across age groups; elderly patients experienced quicker pruritus relief compared to adolescents and adults, while adolescents showed earlier lesion remission by about 3 days. No significant difference was observed across age groups in the time for complete lesion clearance. Additionally, AD duration (less or more than 3 years) did not significantly impact pruritus or lesion remission.

PDE4i monotherapy is effective and safe for chronic hyperplasia lesions in AD across all age groups, and its effectiveness appears to be independent of AD duration.

Photosynthetic bacteria (PSB) has shown significant potential as a drug or drug delivery system owing to their photothermal capabilities and antioxidant properties. Nevertheless, the actualization of their potential is impeded by inherent constraints, including their considerable size, heightened immunogenicity and compromised biosafety. Conquering these obstacles and pursuing more effective solutions remains a top priority. Similar to extracellular vesicles, bacterial outer membrane vesicles (OMVs) have demonstrated a great potential in biomedical applications. OMVs from PSB encapsulate a rich array of bioactive constituents, including proteins, nucleic acids, and lipids inherited from their parent cells. Consequently, they emerge as a promising and practical alternative. Unfortunately, OMVs have suffered from low yield and inconsistent particle sizes. In response, bacteria-derived nanovesicles (BNVs), created through controlled extrusion, adeptly overcome the challenges associated with OMVs. However, the differences, both in composition and subsequent biological effects, between OMVs and BNVs remain enigmatic. In a groundbreaking endeavor, our study meticulously cultivates PSB-derived OMVs and BNVs, dissecting their nuances. Despite minimal differences in morphology and size between PSB-derived OMVs and BNVs, the latter contains a higher concentration of active ingredients and metabolites. Particularly noteworthy is the elevated levels of lysophosphatidylcholine (LPC) found in BNVs, known for its ability to enhance cell proliferation and initiate downstream signaling pathways that promote angiogenesis and epithelialization. Importantly, our results indicate that BNVs can accelerate wound closure more effectively by orchestrating a harmonious balance of cell proliferation and migration within NIH-3T3 cells, while also activating the EGFR/AKT/PI3K pathway. In contrast, OMVs have a pronounced aptitude in anti-cancer efforts, driving macrophages toward the M1 phenotype and promoting the release of inflammatory cytokines. Thus, our findings not only provide a promising methodological framework but also establish a definitive criterion for discerning the optimal application of OMVs and BNVs in addressing a wide range of medical conditions.

During skin aging, the degeneration of epidermal stem cells (EpiSCs) leads to diminished wound healing capabilities and epidermal disintegration. This study tackles this issue through a comprehensive analysis combining transcriptomics and untargeted metabolomics, revealing age-dependent alterations in the Gpx gene family and arachidonic acid (AA) metabolic networks, resulting in enhanced ferroptosis. Selenomethionine (Se-Met) could enhance GPX4 expression, thereby assisting EpiSCs in countering AA-induced mitochondrial damage and ferroptosis. Additionally, Se-Met demonstrates antioxidative characteristics and extensive ultraviolet absorption. For the sustained and controllable release of Se-Met, it was covalently grafted to UV-responsive GelMA hydrogels via AC-PEG-NHS tethers. The Se-Met@GelMA hydrogel effectively accelerated wound healing in a chronological aging mice model, by inhibiting lipid peroxidation and ferroptosis with augmented GPX4 expression. Moreover, in a photoaging model, this hydrogel significantly mitigated inflammatory responses, extracellular matrix remodeling, and ferroptosis in UV-exposed mice. These characteristics render Se-Met@GelMA hydrogel valuable in practical clinical applications.

Chronic nonhealing wounds pose a serious challenge to regaining skin function and integrity. Platelet-derived extracellular vesicles (PEVs) are nanostructured particles with the potential to promote wound healing since they can enhance neovascularization and cell migration and reduce inflammation and scarring. This work provides an innovative overview of the technical laboratory issues in PEV production, PEVs' role in chronic wound healing and the benefits and challenges in its clinical translation. The article also explores the challenges of proper sourcing, extraction techniques and storage conditions, and discusses the necessity of further evaluations and combinational therapeutics, including dressing biomaterials, M2-derived exosomes, mesenchymal stem cells-derived extracellular vesicles and microneedle technology, to boost their therapeutic efficacy as advanced strategies for wound healing.

The scar repair inevitably causes damage of skin function and loss of skin appendages such as hair follicles (HF). It is of great challenge in wound repair that how to intervene in scar formation while simultaneously remodeling HF niche and inducing in situ HF regeneration. Here, chemical reprogramming techniques are used to identify a clinically chemical cocktail (Tideglusib and Tamibarotene) that can drive fibroblasts toward dermal papilla cell (DPC) fate. Considering the advantage of biomaterials in tissue repair and their regulation in cell behavior that may contributes to cellular reprogramming, the artificial HF seeding (AHFS) hydrogel microspheres, inspired by the natural processes of "seeding and harvest", are constructed via using a combination of liposome nanoparticle drug delivery system, photoresponsive hydrogel shell, positively charged polyamide modification, microfluidic and photocrosslinking techniques. The identified chemical cocktail is as the core nucleus of AHFS. In vitro and in vivo studies show that AHFS can regulate fibroblast fate, induce fibroblast-to-DPC reprogramming by activating the PI3K/AKT pathway, finally promoting wound healing and in situ HF regeneration while inhibiting scar formation in a two-pronged translational approach. In conclusion, AHFS provides a new and effective strategy for functional repair of skin wounds.

Adipose mesenchymal stem cell (AMSC)-derived exosomes are promising novel factors for wound repair and regeneration. This study aimed to explore the potential roles and underlying mechanisms of specific miRNA in wound healing using AMSC-derived exosomes as carriers.

The expression profiles of GSE197840 were downloaded to screen for differentially expressed miRNAs (DEmiRNAs), and the corresponding genes of the identified miRNAs were predicted. Next, miRNA-mRNA co-expression networks were constructed and the genes in these networks were subjected to functional analysis. miR-223-3p overexpressed AMSCs were then established to isolate exosomes, and the effects of AMSC-derived exosomes carrying miR-223-3p on wound healing and the related potential mechanisms were further investigated in vivo.

35 DEmiRNAs were identified and a co-expression network containing 22 miRNAs and 91 target genes was constructed. Based on the network, miR-223-3p was the hub node and the genes were significantly enriched in 15 GO terms of biological processes and 14 KEGG pathways, including cAMP, PI3K-Akt, cGMP-PKG, neurotrophin signaling pathway, and dopaminergic synapse. Then, miR-223-3p overexpressed AMSCs-derived exosomes were successfully extracted, and miR-223-3p was found to directly bind with MAPK10. In vivo experiments validated that AMSCs-derived exosomal miR-223-3p could promote wound healing, and up-regulated α-SMA, CD31, COL1A1, COL2A1, COL3A1, and down-regulated MAPK10, TNF-α, IL-β, and IL-6.

AMSC-derived exosomal miR-223-3p may accelerate wound healing by targeting MAPK10.

Wound healing is a dynamic and highly sequential process involving a series of overlapping spatial and temporal phases, including hemostasis, inflammation, proliferation, and tissue remodeling. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal, multidirectional differentiation potential, and paracrine regulation. Exosomes are subcellular vesicular components 30-150 nm in size and are novel carriers of intercellular communication in regulating the biological behaviors of skin cells. Compared to MSCs, MSC-derived exosomes (MSC-exos) possess lower immunogenicity, easy storage, and highly effective biological activity. MSC-exos, mainly derived from adipose-derived stem cells (ADSCs), bone marrow-derived MSCs (BMSCs), human umbilical cord MSCs (hUC-MSCs), and other stem cell types, play a role in shaping the activity of fibroblasts, keratinocytes, immune cells, and endothelial cells in diabetic wounds, inflammatory wound repair, and even wound-related keloid formation. Therefore, this study focuses on the specific roles and mechanisms of different MSC-exos in wound healing, as well as the current limitations and various perspectives. Deciphering the biological properties of MSC-exos is crucial to providing a promising cell-free therapeutic tool for wound healing and cutaneous regeneration.

The incidence of aging-related erectile dysfunction (ED) remains high in the elderly population, and has attracted the attention of the medical community. However, aging-related ED responds poorly to traditional treatments for ED, and its mechanism has not yet been fully clarified. This study sought to explore the potential mechanisms of aging-related ED based on bioinformatics and experimental verification.

A bioinformatics analysis was performed on data from the Gene Expression Omnibus database related to ED and aging, and the associated differentially expressed genes (DEGs) and signaling pathways were identified. Young and aged rats (n=8 per group) were included in the experimental verification study. Erectile function was detected by electrical stimulation of the cavernous nerve. The corpus cavernosum was collected for the follow-up experiments.

A total of 4 hub genes were identified, among which biglycan (BGN) appears to play an important role. The functional enrichment analysis revealed that the extracellular matrix (ECM), especially collagen, related pathways, and the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) pathway were enriched, which was also confirmed by the animal experiments. Impaired erectile function in aged rats was associated with the downregulation of the PI3K/AKT pathway, endothelial dysfunction, and increased fibrosis in the penis.

Erectile function is impaired with aging. The downregulation of the PI3K/AKT pathway, endothelial dysfunction, and increased fibrosis are involved in this process. BGN may be the key gene regulating these changes. Our study extended understandings of the mechanisms of age-related ED and provides new potential treatment ideas.

Secondary to war wounds, trauma, etc., hypertrophic scar formation is the cause of an excessive proliferation of fibroblasts and accumulation of collagen fibers, which might affect cosmetic appearance, and could cause malignant transformation. miRNAs play an important role in disease regulation via inhibiting post-transcriptional protein translation by targeting and binding to the 3' UTR region of mRNA. Here we explore the mechanism and interventions of scar formation from the perspective of miRNA.

Hypertrophic scar-associated differential miRNAs were screened by analyzing sequencing data of normal skin and hypertrophic scar, and verified by RT-qPCR. Signaling pathways that may be influenced by differentially miRNAs were analyzed using KEGG and GO. miRNA mimics were used to explore the effects of miRNAs on SMAD signaling pathway proteins. Dual-luciferase assays were used to explore the targeted binding of miRNAs. The mimics of the miRNA were used to explore the impact of miRNAs on the proliferation, migration, apoptosis and collagen synthesis levels of hypertrophic scar fibroblasts. The scar model of rabbit ear was used to verify the influence of miRNA on wound healing and scar formation in vivo.

Expression of miR-182-5p was found to be considerably decreased in hypertrophic scars and fibroblasts. miR-182-5p was found to act mainly by targeting the 3'UTR region of SMAD4, but not SMAD1 or SMAD3. miR-182-5p overexpression may drastically suppress the proliferation and migration of fibroblasts, accompanied by enhanced apoptosis and reduced collagen fiber synthesis. The overexpression of miR-182-5p in in vivo experiments could effectively inhibit hypertrophic scar formation without affecting the speed and quality of wound healing.

miR-182-5p inhibits hypertrophic scar formation by decreasing the proliferation and migration of fibroblasts via SMAD4 pathway, and is expected to become a novel hypertrophic scar therapeutic target.

Pressure injury often seriously affects the life quality of aged patients, especially the long-term bedridden casualties. Widely adopted by different disciplines, negative pressure suction has its role in pressure injury. Microskin implantation has been demonstrated powerful in increasing the expansion ratio of donor area-derived skin and accelerating wound healing by forming "skin islands". The study was designed to evaluate the efficacy and safety of additional use of bedside microskin implantation in the palliative care of pressure injury of aged patients who cannot tolerate surgical treatment as a supplement for standard negative pressure suction. An open-label within-patient RCT was conducted in aged patients with pressure injury. Sixteen patients were enrolled. After granulation tissues formed, half of a pressure injury was randomised to receive the negative pressure suction as the control group, and the other half exposed to additional bedside microskin implantation as the experimental group. Efficacy was evaluated within 1 month after treatment, and the primary endpoints included the wound healing rate and pressure ulcer scale for healing (PUSH) scores. The secondary outcomes included survival rate of implanted microskin, pain intensity assessment, satisfaction surveys from patients or their family, and pressure ulcer healing complications. Sixteen patients completed the study. After 14 days of operation, 5.63 ± 1.78 out of 10 pieces of implanted microskin survived and formed neonatal epithelium. The wound healing rates of the control group and the experimental group at 1 month were (26.17 ± 9.03%) and (35.95 ± 16.02%), respectively (P < .01). The mean PUSH score before the surgery was 12.38 ± 2.23. At 1 month after surgery, the mean difference of PUSH score from baseline was 2.13 ± 0.96 in the control group and 2.81 ± 0.83 in the experimental group (P < .01). The treatment of microskin implantation did not cause additional pain or complications to the patients. Accompanied by a better ulcer status, the majority of patients or their guardians have a high degree of acceptance towards the microskin implantation. Bedside microskin implantation could accelerate wound healing with lower PUSH scores. As a complementary palliative treatment, supplementary microskin implantation is effective and well tolerated.