Shoeblackplant extract-loaded carboxymethyl cellulose/collagen scaffolds seeded with adipose-derived stem cells enhance diabetic wound healing via immunomodulation and angiogenic pathways.

ZnO-integrated konjac glucomannan/Bletilla striata hydrogel with antibacterial, anti-inflammatory, and pro-angiogenic properties for accelerated infected wound healing.

Zinc-chelated cuttlefish ink melanin nanoparticle-complexed sprayable chitosan-based hydrogel for promoting infected wound healing.

Decellularized matrix (dECM) derived from small intestine submucosa (SIS) has been increasingly used in tissue engineering and regenerative medicine. While dECM provides cell-adhesive and protease-labile sequences to support cell-matrix interactions, its crosslinking into hydrogels has been largely limited to temperature-induced gelation, which offers limited tunability. To address this challenge, we previously reported the synthesis of bovine decellularized SIS-norbornene (dSIS-NB) for crosslinking into cytocompatible thiol-norbornene hydrogels with pro-angiogenic and pro-vasculogenic properties. In this study, we conducted proteomic profiling to analyze the protein compositions of bovine dSIS and dSIS-NB. In addition to various collagens, we discovered that bovine dSIS contained significant amounts of fibrillin-I, a glycoprotein stabilized by intra- and inter-molecular disulfide bonds. We leveraged these disulfide bonds to fabricate 'self-clickable' dSIS-NB thiol-norbornene hydrogels without the need for additional thiol-bearing crosslinker (e.g., 4-arm poly(ethylene glycol)-thiol). Furthermore, we exploited thiol-disulfide exchange in self-clickable dSIS-NB hydrogels to enable light-induced spatiotemporal tuning of hydrogel stiffness and labeling of bioactive ligands. Finally, the dynamic and self-clickable dSIS-NB hydrogels were used as an in vitro cell culture model to study local vascular compression and as an injectable, cell-laden matrix to treat volumetric muscle loss.

Diabetic ulcers (DUs) are a main category of nonhealing chronic wounds that tend to be vulnerable and prone to recurrence, posing a significant clinical challenge for DUs healing. DUs are frequently plagued by bacterial infections, oxidative stress, persistent inflammation, suppressed angiogenesis, and reduced growth factor expression, ultimately leading to persistent barriers to tissue regeneration and even amputation. Herein, we developed a multifunctional polysaccharide-based conductive hydrogel microneedle patch (MN-EP) integrating hyaluronic acid (HA) needle shafts, carboxymethyl chitosan-oxidized HA (CMCS-OHA) hydrogel backing, and oregano essential oil (OEO)-loaded polypyrrole (PPy) nanoparticles (EP NPs). MN-EP exhibited sufficient mechanical strength to penetrate stratum corneum, favorable conductivity matching skin tissue due to EP NPs, broad-spectrum antibacterial activity (nearly 100% against Staphylococcus aureus and Escherichia coli), and potent antioxidant capacity. It was demonstrated that MN-EP can scavenge intracellular reactive oxygen species (ROS), induce macrophage polarization toward the anti-inflammatory M2 phenotype, and promote fibroblast migration. In diabetic rats with infected full-thickness wounds, the electroactive MN-EP effectively eliminated harmful microorganisms at the wound site and modulated the immune microenvironment, thereby accelerating the resolution of inflammation, enhancing collagen deposition, and upregulating angiogenesis markers (CD31, VEGF), which promoted vascular and tissue regeneration and accelerated wound closure (98.28% by day 14). Overall, the multifunctional conductive hydrogel microneedle platform with antibacterial, anti-inflammatory, and pro-angiogenic properties represents a promising strategy for infected chronic diabetic wound healing.

The GG/TA-Zn composite hydrogel enhances diabetic bone defect healing via inflammation regulation and vascular-bone synergistic effects.

Magnesium phosphate mineralized Ce6 composite hydrogel with photodynamic therapy-mediated antibacterial, anti-inflammatory, and pro-angiogenic properties for application in infected wound healing.

Abstract Background Little is known about the pathological crosstalk between the skeletal muscle and vascular network in Peripheral Artery Disease (PAD). Exosomes are nano-sized vesicles that shuttle microRNA signalling messages between cells, with evidence that the micro-environment can alter their miRNA content. Methods Exosomes were isolated from normoxic C2C12 myotubes (MTnorm) and myotubes exposed to simulated ischaemia (MThyp) through ultracentrifugation. Exosomes were then co-cultured with human umbilical vein endothelial cells (HUVECs) and uptake assessed through fluorescence image analysis and flow cytometry. Aortic ring and angiogenesis assays were used to determine the angiogenic potential of MThyp exosomes. RNA Sequencing was used to identify significantly differentially expressed miRNA in MThyp exosomes followed by in silico enrichment analysis using Ingenuity Pathway Analysis software to determine which pathways are targeted. Results Exosomes secreted by MTnorm and MThyp cells were taken up by over 80% HUVECs in 24 h. MThyp exosomes significantly increase HUVEC tube length (P = 0.037) compared to MTnorm exosomes and number of loops (P = 0.012) in the tube formation and aortic ring assays. RNA-Sequencing revealed 30 significantly upregulated miRNA in MThyp exosomes, of which, miRNA-181d was identified as a promoter of angiogenesis through inhibition of CDKN1B and TIMP3. Discussion MThyp exosomes are taken up by endothelial cells and have proangiogenic properties compared with MTnorm exosomes through overexpression of miRNA-181d. The contribution of this muscle-endothelial cell crosstalk in the pathogenesis of PAD requires further investigation.

Patients' quality of life is severely compromised by full-thickness oral mucosal abnormalities, and traditional treatment approaches are severely hampered by the dynamic wet environment and tissue heterogeneity. Hydrogels have demonstrated remarkable efficacy in promoting skin wound repair; however, their ability to adhere effectively and sustain functionality within the oral cavity remains inadequate. This work used hyaluronic acid (HA), 3-aminophenylboronic acid (3-APBA), tannic acid (TA), and deferoxamine (DFO) as major components to create a multifunctional hydrogel called HPTA@DFO (abbreviated as HTD), which was inspired by the wet adhesion mechanism of marine mussels. This system was created using dynamic covalent cross-linking (Schiff base and borate ester linkages), which gave it tissue-conformable adhesive qualities, injectability, and the ability to heal itself. The antibacterial, antioxidant, anti-inflammatory, and pro-angiogenic properties of the HTD hydrogel were confirmed by experimental data. In a rat model of full-thickness oral mucosal defects, the HTD hydrogel effectively promoted wound healing and tissue regeneration, demonstrating good biocompatibility. This work offers an innovative design approach and experimental basis for creating intelligent dressings appropriate for the intricate oral environment.

BackgroundVascular injury is a major contributor to the development of cardiovascular diseases. Following vascular damage, macrophages migrate to the injury site and, during the later stages of vascular repair, secrete cytokines such as interleukin-10 (IL-10) and transforming growth factor-β1a (TGFB1A), thereby promoting vascular regeneration. Previous studies have demonstrated that macrophage recruitment to sites of tissue injury is mediated by the CXCR4A-CXCL12B signaling axis. In a screening of traditional Chinese medicinal herbs for cardiovascular therapeutic potential, Salvia miltiorrhiza root was identified as a promising source of bioactive compounds capable of enhancing vascular repair through modulation of the CXCR4A-CXCL12B axis.MethodsEstablishing a vascular injury model in transgenic zebrafish lines Tg (flk1:eGFP; gata1:dsRed) using a two-photon microscopy laser system. Dynamic monitoring of vascular repair via two-photon microscopy. Evaluate macrophage migration capacity in a Tg (mpeg1:eGFP) zebrafish vascular injury model using confocal microscopy. Detection of il-10 and tgfb1a expression released by macrophages via qPCR experiments. Detect CXCR4A-CXCL12B expression at the site of zebrafish vascular injury via fluorescence in situ hybridization coupled with antibody staining.ResultsWe confirm that compounds from the selected extract promote macrophage migration to vascular injury sites by upregulating the CXCR4A-CXCR12B signaling axis. This process accelerates repair of damaged blood vessels in zebrafish by inducing the release of cytokines such as il-10 and tgfb1a.ConclusionsThis study confirms that Salvia miltiorrhiza, a traditional Chinese medicinal plant, is a valuable source of bioactive compounds with pro-angiogenic properties. Our findings provide scientific support for the traditional use of Salvia miltiorrhiza active components in treating vascular injuries.

Chronic diabetic wounds are challenging to treat due to persistent inflammation, oxidative stress, impaired angiogenesis, and dysregulated matrix remodelling. Hydrogen sulphide (H2S) has emerged as a therapeutic mediator with antioxidant, anti-inflammatory, and pro-angiogenic properties; however, its clinical translation is limited by volatility and a short biological half-life. Controlled delivery systems, such as hydrogels, are therefore required to harness its potential. This study aimed to develop and evaluate a sodium 2-acrylamido-2-methylpropane sulfonate (Na-AMPS)-based adhesive hydrogel incorporating AP39, a mitochondria-targeted H2S donor, for sustained localised delivery and promotion of wound healing. Hydrogel formulations were characterised for rheological behaviour, adhesion, swelling, and AP39 release. Cytocompatibility was assessed in human umbilical vein endothelial cells (HUVECs); human dermal fibroblasts, adult (HDFa); and keratinocytes. Anti-inflammatory, antioxidant, and matrix-modulatory effects were evaluated via interleukin-6 and 8 (IL-6/IL-8) secretion, reactive oxygen species (ROS) levels, mitochondrial membrane potential, matrix metalloproteinase-9 (MMP-9), and transforming growth factor-beta (TGF-β). Functional wound healing activity was assessed using tube formation and scratch assays in endothelial cells. AP39-loaded hydrogels exhibited predominantly elastic, shear-thinning behaviour, strong adhesion, rapid hydration, and sustained release of AP39 (11.63 ± 1.20% over 24 h). Across all cell types, 500 nM concentrations of AP39 were well tolerated. In diabetic-like stress conditions, AP39 significantly decreased ROS in HUVECs (50122 ± 5999 to 33,087 ± 1865 AU; p < 0.0001) and HDFa cells (41,367 ± 4225 to 29,813 ± 2406 AU; p < 0.0001). AP39 improved mitochondrial membrane potential in both cell types (p < 0.01-0.001) and decreased pro-inflammatory cytokines. IL-6 decreased in HUVECs (96.05 ± 4.22 pg/mL to 60.99 ± 4.21 pg/mL; p < 0.0001) and HDFa cells (77.54 ± 8.94 pg/mL to 52.25 ± 6.78 pg/mL; p < 0.001), whilst in HDFa cells, MMP-9 was reduced (419.4 ± 25.51 pg/mL to 174 ± 15.1 pg/mL; p < 0.0001). Finally, wound closure was enhanced in HUVECs. The AP39-loaded Na-AMPS hydrogel represents a multifunctional wound dressing capable of controlled H2S delivery, mechanical stability, and biological activity to support tissue repair in diabetic wound environments. These results highlight this gel's therapeutic potential for diabetic wound treatment.

Chronic refractory wounds, such as diabetic foot ulcers, present significant clinical challenges due to a dysregulated healing microenvironment. Extracellular vesicles (EVs) have emerged as promising therapeutic agents owing to their pro-angiogenic, anti-inflammatory, and regenerative properties. However, their clinical translation is hampered by rapid clearance and instability at the wound site. Hydrogel-based delivery systems offer an effective strategy to overcome these limitations by providing a protective and tunable platform for sustained EVs release. This review systematically synthesizes contemporary advances in EVs hydrogel (EVH) systems for chronic wound therapy. We critically evaluate design strategies encompassing various hydrogel matrices (natural, synthetic, and smart responsive), engineering approaches for EVs modification, and controlled-release mechanisms that collectively enhance therapeutic efficacy. By integrating findings from preclinical studies across diverse wound models, we highlight the synergistic roles of EVH systems in promoting angiogenesis, modulating immune responses, and accelerating tissue regeneration. Furthermore, this review addresses key translational challenges, including scalable EVs production, standardization, biosafety, and regulatory pathways. Finally, we provide forward-looking perspectives on the clinical translation of next-generation, intelligent EVH systems, aiming to bridge the gap between innovative design and practical therapeutic application.

Altered extracellular matrix (ECM), a hallmark of solid tumors, affects cellular survival, migration and differentiation. Typically viewed as tumor-suppressive, evidence suggests that apoptosis can also generate pro-tumoral signals. We previously showed that ECM from high-grade astrocytomas induces extensive endothelial anoikis, while a surviving subpopulation fails to form tubular structures (tubulogenesis-defective endothelial cells, or TDECs). We combined functional assays with whole-cell proteomics to investigate this response. Using real-time video microscopy, we found that apoptotic endothelial cells induced by tumor ECM attracted migrating endothelial cells and guided sprouting. Conditioned media from apoptotic endothelial cells contained a 2.8-fold increase in extracellular vesicles (EVs) relative to autologous ECM-primed endothelial cells. Although both EV populations improved TDEC tubulogenesis, only EVs produced upon tumor-ECM stimulation induced TDEC migration-a property lost when using EVs secreted by endothelial cells growing on TN-C-depleted matrices. Proteomic profiling revealed that TDECs shift from an adhesion-anchored to a microtubule-rich and glycolytically rewired phenotype, with upregulation of vesicle-trafficking regulators (ARF1/3/4, ANXA2/5), migration drivers (RAC1/3, RHOA/C, WDR1, FSCN1) and glycolytic enzymes (ENO1, ALDOA, PKM, LDHA), alongside the suppression of integrin- and cytoskeletal-anchoring proteins. Collectively, these findings indicate that tumor-ECM-driven endothelial apoptosis generates reversible reprogramming and an EV-mediated autocrine mechanism that may favor angiogenic balance.

Wound healing is a highly intricate biological process that progresses through sequential phases: haemostasis, inflammation, proliferation, and remodelling, each regulated by a series of cellular and molecular mechanisms. The healing process is often impaired by chronic inflammation, oxidative stress, infections, and other pathological conditions, resulting in delayed tissue regeneration. Natural flavonoids, with their antioxidant, anti-inflammatory, antimicrobial, and pro-angiogenic properties, have gained significant attention as potential therapeutic agents for enhancing wound repair. However, their clinical application remains constrained by challenges such as poor water solubility, low bioavailability, rapid metabolism, and instability under physiological conditions. To address these limitations, polymer-based delivery systems-including hydrogels, nanofibers, nanoparticles, and hybrid formulations-have been developed using natural, synthetic, and semi-synthetic polymers. These systems offer improved drug encapsulation, sustained release, targeted delivery, and enhanced stability, thereby optimizing the therapeutic potential of flavonoids in wound management. This review comprehensively discusses the characteristics, selection criteria, and mechanisms of polymer and hybrid systems employed for flavonoid delivery, along with their synergistic effects on tissue regeneration. Furthermore, it provides a translational framework for designing multifunctional wound healing platforms, highlighting the promise of polymeric carriers in overcoming pharmacokinetic barriers and achieving improved clinical outcomes.

Ligand-metal charge transfer-enabled copper-gallate nanozyme rescue oxidative stressed reparative cells for inflammatory dental tissue regeneration.

Angiogenesis is critical for effective wound healing and relies on the successful coordination of various cell types, including endothelial cells, macrophages, and fibroblasts. Adipose-derived stem cell extracellular vesicles (ADSC-EVs) have demonstrated proangiogenic properties and have been posited as a novel therapeutic to aid wound healing; however, their functional impact within human-derived multicellular models remains largely uncharacterized. This study explores the development and application of a 3D multicellular in vitro model to assess the effects of ADSC-EVs on vascularization in the context of wound healing. 3D multicellular in vitro models were developed by coculturing human umbilical vein endothelial cells (HUVECs), monocyte-derived macrophages, and fibroblasts within Matrigel to recapitulate the invivo wound healing microenvironment. A five-color confocal microscopy panel was developed to visualize each cell type and EVs within the models. The optimized models were then treated with ADSC-EVs or control to determine their impact on angiogenesis and cell colocalization. We determined that vessel formation was significantly enhanced when HUVECs were cocultured in multicellular models compared with monocultures, with the greatest effect observed in the full three-cell-type model. This effect was even more pronounced with the addition of ADSC-EVs. ADSC-EV treatment also enhanced macrophage colocalization within endothelial structures. This study developed a multicellular model that can be used for future work assessing wound healing in vitro and will be additive to currently used single-cell and invivo models. We have applied these models to demonstrate that ADSC-EVs significantly enhance tube formation in HUVECs and the development of tissue-like structures in multicell systems, highlighting their potential as a promising therapeutic approach for improving wound healing.

Background: Mesenchymal stem cells (MSCs) exhibit a high capacity for differentiation, possess anti-inflammatory and proangiogenic properties, and stimulate the growth and proliferation of neighboring cells. MSCs are a promising tool in regenerative medicine. However, the molecular mechanisms underlying the properties of these cells are not yet fully understood. Gene expression in MSCs influences their characteristics and differentiation potential. Therefore, it is essential to investigate factors affecting gene expression as well as those activating signaling pathways, which will enable more effective and individualized applications of MSCs. In this study, we aimed to identify signaling pathways involved in gene expression in umbilical cord-derived MSCs (UC-MSCs) that may be altered by maternal diabetes and hypothyroidism during pregnancy. Methods: The research material consisted of UC-MSCs. Samples obtained from nine participants were analyzed. UC-MSCs were isolated and cultured, and RNA was extracted. The isolated RNA was used for microarray-based gene expression analysis. Subsequently, pathway enrichment analysis was performed to identify the signaling pathways involved. Results: In the diabetes group, 340 genes (0.71%) were upregulated, while 268 genes (0.56%) were downregulated compared with UC-MSCs from the control group. In the diabetes group, the most compact module was composed of proteins associated with WNT/planar cell polarity (WNT/PCP) signaling. The second module included genes related to smooth muscle activity. In the hypothyroidism group, an association was identified between the extracellular matrix organization pathways (GO:0030198) and the extracellular structure organization (GO:0043062) pathways. Moreover, in this group, increased expression of MMP1, MMP10, and GREM1 was observed. Conclusions: In summary, our study demonstrated the impact of diabetes and hypothyroidism on gene expression in UC-MSCs. We also observed the activation of distinct signaling pathways depending on the presence of these conditions. However, this work represents a preliminary screening, and the results should be validated by PCR in a larger cohort.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disease associated with long-term glucocorticoid use, characterized by impaired bone metabolism and vascular insufficiency. Bilobalide (BB), a natural sesquiterpene from Ginkgo biloba, exhibits anti-apoptotic, antioxidant, and pro-angiogenic properties, yet its role in SONFH remains unclear. We integrated network pharmacology and molecular docking to predict the targets and pathways of BB in SONFH. Key targets were validated using molecular docking software. For in vivo experiments, a rat SONFH model was established using methylprednisolone (MPS), and BB was administered orally. Micro-CT, H&E staining, TUNEL assay, and immunohistochemistry were employed to evaluate bone microstructure, apoptosis, and the expression of osteogenic and angiogenic markers. Immunofluorescence was used to assess HIF-1α expression in rat femoral head tissues. For in vitro experiments, MC3T3-E1 osteoblasts were treated with dexamethasone(DEX) and BB. Cell viability was detected using the CCK-8 assay, and the protein levels of the HIF-1α and ERK pathways were examined by Western blot. Network pharmacology identified 94 common targets between BB and SONFH, with enrichment in HIF-1 and ERK signaling pathways. Molecular docking confirmed strong binding affinities between BB and core targets. In MPS-induced rats, BB treatment significantly improved bone mineral density, trabecular microstructure, and reduced osteocyte apoptosis. BB also upregulated HIF-1α, Runx2, OCN, CD31, and VEGF expression, indicating enhanced osteogenesis and angiogenesis. In vitro, BB rescued dexamethasone-induced suppression of osteoblast viability and upregulated the ERK/HIF-1α pathway. Bilobalide attenuates SONFH progression by activating the ERK/HIF-1α signaling pathway, promoting osteogenesis and angiogenesis, and reducing osteocyte apoptosis. These findings highlight BB as a promising candidate for SONFH prevention and support the utility of network pharmacology in mechanistic natural product research.

Mesoporous silica (MS) is widely recognized as a local drug delivery system in bone-related diseases. Although MS enables controlled or sustained release and improved bioavailability of therapeutic agents, its limited native osseointegration capacity remains a critical barrier to effective bone regeneration. Numerous engineering strategies have therefore been proposed to enhance its biological performance. This scoping review protocol aims to collect studies, published from January 2015 onwards, that report evidence on the osseointegration potential (i.e., osteoconductive, osteoinductive, or proangiogenic properties) of MS bone drug delivery systems. Studies indexed in PubMed, Scopus, and Embase will be screened to identify the strategies used to improve MS-mediated bone regeneration, including structural modifications, formulation into composites, and incorporation of bioactive molecules. A structured analytical framework will be applied to explore how specific design approaches relate to biological outcomes across experimental models in vitro, in vivo, or ex vivo. The resulting scoping review will identify trends and knowledge gaps in strategies intended to enhance the osseointegration of MS bone drug delivery systems, supporting their future development and rational optimization for bone repair.

Salidroside derivative SHPL-49 accelerates cutaneous wound healing in diabetic mice by modulating macrophage-mediated TGF-β1/Smad2/3 signaling pathway.