Diabetic Wound Model Research Articles

Loureirin B Accelerates Diabetic Wound Healing by Promoting TGFβ/Smad-Dependent Macrophage M2 Polarization: A Concerted Analytical Approach Through Single-Cell RNA Sequencing and Experimental Verification.

Diabetic wound (DW) represent a significant clinical challenge and often fail to heal effectively. Loureirin B (LB), a flavonoid extracted from dragon's blood, has shown potential by influencing macrophage polarization and promoting wound healing. However, its mechanisms and efficacy in DW remain to be explored. This study employed single-cell RNA sequencing to analyze the classification of cells in diabetic foot ulcers and to identify the related mechanisms influenced by macrophages. Molecular docking was used to predict the interactions of LB with key proteins in the TGFβ/Smad signaling pathway. The effects of LB on macrophage polarization and wound healing were further validated through invitro and invivo experiments using a DW model. Single-cell analysis identified specific macrophage subtypes involved in the DW healing process and highlighted the role of the TGFβ/Smad pathway. Molecular docking suggested the potential action within the TGFβ/Smad pathway. Invitro studies showed that under high glucose conditions, LB promoted macrophage polarization from pro-inflammatory M1 to healing-promoting M2 and ECM production in fibroblasts by activating TGF-β/Smad signaling. Invivo, LB treatment enhanced wound healing rates in diabetic mice and promoted macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF-β/Smad signaling. LB regulates macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF-β/Smad signaling to promote DW healing. These findings suggest that LB could be a potential therapeutic agent for improving DW healing, emphasizing the need for further clinical studies to explore its efficacy and mechanisms in human subjects.

Metformin Syncs CeO2 to Recover Intra- and Extra-Cellular ROS Homeostasis in Diabetic Wound Healing.

Excessive generation of reactive oxygen species (ROS) poses a huge obstacle to the healing process of diabetic wounds, resulting in chronic, non-healing wounds. While numerous anti-ROS therapeutics have been developed, satisfied intra- and extra- cellular ROS homeostasis is hard to be established in diabetic wounds. To address this issue, a nanoparticle via loading metformin and CeO2 into mesoporous silica (MSN@Met-CeO2) is designed and synthesized, which is then encapsulated within ROS-responsive hydrogel and shaped as microneedles (MNs) for better application in diabetic wounds. Interestingly, a unique metformin-cerium chelate (Ce· 3Metformin) is formed during the synthesis of MSN@Met-CeO2 MN, which significantly strengthened the inhibitory effect of metformin on mitochondrial complex I. With the presence of Ce· 3Metformin, MSN@Met-CeO2 MN performed a remarkable effect on intracellular mtROS reduction as well as extracellular ROS elimination, the latter is primarily accomplished through the dissociative CeO2 in MSN@Met-CeO2 MN. In the mouse diabetic wound model, MSN@Met-CeO2 MN exhibited a superior pro-healing effect with accelerated inflammation resolution and enhanced angiogenesis, thus highlighting its significant potential for clinical application.

Collaborative Enhancement of Diabetic Wound Healing and Skin Regeneration by Recombinant Human Collagen Hydrogel and hADSCs.

Stem cell-based therapies hold significant promise for chronic wound healing and skin appendages regeneration, but challenges such as limited stem cell lifespan and poor biocompatibility of delivery systems hinder clinical application. In this study, an in situ delivery system for human adipose-derived stem cells is developed (hADSCs) to enhance diabetic wound healing. The system utilizes a photo-crosslinking recombinant human type III collagen (rHCIII) hydrogel to encapsulate hADSCs, termed the hADSCs@rHCIII hydrogel. This hydrogel undergoes local crosslinking at the wound site, establishing a sturdy 3D niche suitable for stem cell function. Consequently, the encapsulated hADSCs exhibit strong attachment and spreading within the hydrogels, maintaining their proliferation, metabolic activity, and viability for up to three weeks in vitro. Importantly, in vivo studies demonstrate that the hADSCs@rHCIII hydrogel achieves significant in situ delivery of stem cells, prolonging their retention within the wound. This ultimately enhances their immunomodulatory capabilities, promotes neovascularization and granulation tissue formation, facilitates matrix remodeling, and accelerates healing in a diabetic mouse wound model. Collectively, these findings highlight the potential of the conveniently-prepared and user-friendly hADSCs@rHCIII hydrogel as a promising therapeutic approach for diabetic wound treatment and in situ skin regeneration.

Zinc-based Polyoxometalate Nanozyme Functionalized Hydrogels for optimizing the Hyperglycemic-Immune Microenvironment to Promote Diabetic Wound Regeneration.

In diabetic wounds, hyperglycemia-induced cytotoxicity and impaired immune microenvironment plasticity directly hinder the wound healing process. Regulation of the hyperglycemic microenvironment and remodeling of the immune microenvironment are crucial. Here, we developed a nanozymatic functionalized regenerative microenvironmental regulator (AHAMA/CS-GOx@Zn-POM) for the effective repair of diabetic wounds. This novel construct integrated an aldehyde and methacrylic anhydride-modified hyaluronic acid hydrogel (AHAMA) and chitosan nanoparticles (CS NPs) encapsulating zinc-based polymetallic oxonate nanozyme (Zn-POM) and glucose oxidase (GOx), facilitating a sustained release of release of both enzymes. The GOx catalyzed glucose to gluconic acid and (H₂O₂), thereby alleviating the effects of the hyperglycemic microenvironment on wound healing. Zn-POM exhibited catalase and superoxide dismutase activities to scavenge reactive oxygen species and H₂O₂, a by-product of glucose degradation. Additionally, Zn-POM induced M1 macrophage reprogramming to the M2 phenotype by inhibiting the MAPK/IL-17 signaling diminishing pro-inflammatory cytokines, and upregulating the expression of anti-inflammatory mediators, thus remodeling the immune microenvironment and enhancing angiogenesis and collagen regeneration within wounds. In a rat diabetic wound model, the application of AHAMA/CS-GOx@Zn-POM enhanced neovascularization and collagen deposition, accelerating the wound healing process. Therefore, the regenerative microenvironment regulator AHAMA/CS-GOx@Zn-POM can achieve the effective conversion of a pathological microenvironment to regenerative microenvironment through integrated control of the hyperglycemic-immune microenvironment, offering a novel strategy for the treatment of diabetic wounds.

Multifunctional Hydrogel Microneedle Patches Modulating Oxi-inflamm-aging for Diabetic Wound Healing.

Oxidative stress, chronic inflammation, and immune senescence are important pathologic factors in diabetic wound nonhealing. This study loads taurine (Tau) into cerium dioxide (CeO2) to develop CeO2@Tau nanoparticles with excellent antioxidant, anti-inflammatory, and anti-aging properties. To enhance the drug penetration efficiency in wounds, CeO2@Tau is encapsulated in gelatin methacryloyl (GelMA) hydrogel to prepare CeO2@Tau@Hydrogel@Microneedle (CTH@MN) patch system. Microneedle technology achieves precise and efficient delivery of CeO2@Tau, ensuring their deep penetration into the wound tissue for optimal efficacy. Rigorous in vitro and in vivo tests have confirmed the satisfactory therapeutic effect of CTH@MN patch on diabetic wound healing. Mechanistically, CTH@MN attenuates oxidative damage and inflammatory responses in macrophages by inhibiting the ROS/NF-κB signaling pathway. Meanwhile, CTH@MN activated autophagy-mediated anti-aging activity, creating a favorable immune microenvironment for tissue repair. Notably, in a diabetic mouse wound model, the multifunctional CTH@MN patch significantly promotes wound healing by systematically regulating the oxidation-inflammation-aging (oxi-inflamm-aging) pathological axis. In conclusion, the in-depth exploration of the CTH@MN system in this study provides new strategies and perspectives for treating diabetic non-healing wounds.

Granular Porous Nanofibrous Microspheres Enhance Cellular Infiltration for Diabetic Wound Healing.

Diabetic foot ulcers (DFUs) are a significant challenge in the clinical care of diabetic patients, often necessitating limb amputation and compromising the quality of life and life expectancy of this cohort. Minimally invasive therapies, such as modular scaffolds, are at the forefront of current DFU treatment, offering an efficient approach for administering therapeutics that accelerate tissue repair and regeneration. In this study, we report a facile method for fabricating granular nanofibrous microspheres (NMs) with predesigned structures and porosities. The proposed technology combines electrospinning and electrospraying to develop a therapeutic option for DFUs. Specifically, porous NMs were constructed using electrospun poly(lactic-co-glycolic acid) (PLGA):gelatin short nanofibers, followed by gelatin cross-linking. These NMs demonstrated enhanced cell adhesion to human dermal fibroblasts (HDF) during an in vitro cytocompatibility assessment. Notably, porous NMs displayed superior performance owing to their interconnected pores compared to nonporous NMs. Cell-laden NMs demonstrated higher Young's modulus values than NMs without loaded cells, suggesting improved material resiliency attributed to the reinforcement of cells and their secreted extracellular matrix. Dynamic injection studies on cell-laden NMs further elucidated their capacity to safeguard loaded cells under pressure. In addition, porous NMs promoted host cell infiltration, neovascularization, and re-epithelialization in a diabetic mouse wound model, signifying their effectiveness in healing diabetic wounds. Taken together, porous NMs hold significant potential as minimally invasive, injectable treatments that effectively promote tissue integration and regeneration.

Self-Growing Hydrogel Bioadhesives for Chronic Wound Management.

Hydrogel bioadhesives have emerged as a promising alternative to wound dressings for chronic wound management. However, many existing bioadhesives do not meet the functional requirements for efficient wound management through dynamically mechanical modulation, due to the reduced wound contractibility, frequent wound recurrence, incapability to actively adapt to external microenvironment variation, especially for those gradually-expanded chronic wounds. Here, a self-growing hydrogel bioadhesive (sGHB) patch that exhibits instant adhesion to biological tissues but also a gradual increase in mechanical strength and interfacial adhesive strength within a 120-h application is presented. The gradually increased mechanics of the sGHB patch could effectively mitigate the stress concentration at the wound edge, and also resist the wound expansion at various stages, thus mechanically contracting the chronic wounds in a programmable manner. The self-growing hydrogel patch demonstrated enhanced wound healing efficacy in a mouse diabetic wound model, by regulating the inflammatory response, promoting the faster re-epithelialization and angiogenesis through mechanical modulation. Such kind of self-growing hydrogel bioadhesives have potential clinical utility for a variety of wound management where dynamic mechanical modulation is indispensable.

Efficacy and mechanism of Schisandra chinensis active component Gomisin A on diabetic skin wound healing: network pharmacology and in vivo experimental validation

Ethnopharmacological relevanceSchisandra chinensis (Turcz.) Baill., a common traditional Chinese herbal medicine, has been used for the treatment of diabetes mellitus and its complications. However, the major active component for treating diabetic foot ulcers, a serious complication of diabetes mellitus, was unclear. This study aimed to predict the treatment effect of the active components in Schisandra chinensis against diabetic skin wound using network pharmacology and to confirm the underlying mechanism using a diabetic skin wound model in vivo. Aim of the studyTo study the effects and underlying mechanisms of Schisandra chinensis and its main component Gomisin A on diabetic skin wound healing by network pharmacology and high-fat diet (HFD)-induced obese mice model in vivo. Materials and methodsTo determine the effectiveness of Schisandra chinensis on diabetic skin wound, network pharmacology was first used. Components of Schisandra chinensis were obtained from the Traditional Chinese Medicine Systems Pharmacology database. The active components were further verified through absorption, distribution, metabolism and excretion. The potential targets of the active components were identified from the Traditional Chinese Medicine Systems Pharmacology, SwissTargetPrediction, TargetNet, and the Comparative Toxicogenomics Database. Targets related to diabetic skin wound were collected from the GeneCards, OMIM, DisGeNET, and PharmGKB databases. The interaction network formed by the intersection of the two datasets was analyzed using Gephi. Network-based proximity was used to predict the network distance between the active components of Schisandra chinensis and diabetic skin wound. Gomisin A was found to have the lowest Z-score and was administered either orally or via topical injection to HFD-induced obese mice daily until the wounds healed, and its effects on skin wound healing were evaluated. ResultsOnly five active ingredients of Schisandra chinensis were screened in our system: Gomisin A, Longikaurin A, Deoxyharringtonine, Wuweizisu C, and Interiotherin B, which can regulate biological processes related to diabetic skin wound, including positive regulation of phosphorous metabolic process, positive regulation of cell migration, and response to wounding. Network proximity analysis found that Gomisin A has the closest distance-based Z-score among the diabetic skin wound modules and drug targets in the human protein-protein interaction network. The HFD-induced obese mice model further revealed that Gomisin A accelerated skin wound healing by increasing insulin sensitivity and decreasing the advanced glycation end-products mediated toll-like receptor 4 (TLR4)-p38 MAPK-IL6 inflammation signaling pathway. ConclusionsThe network pharmacology and in vivo studies indicated that Gomisin A from Schisandra chinensis played a crucial role in improving diabetic skin wound healing.

Multifunctional Photothermal Nanorods for Targeted Treatment of Drug-Resistant Bacteria-Induced Wound Healing.

The challenge of drug-resistant bacteria-induced wound healing in clinical and public healthcare settings is significant due to the negative impacts on surrounding tissues and difficulties in monitoring the healing progress. We developed photothermal antibacterial nanorods (AuNRs-PU) with the aim of selectively targeting and combating drug-resistant Pseudomonas aeruginosa (P. aeruginosa). The AuNRs-PU were engineered with a bacterial-specific targeting polypeptide (UBI29-41) and a bacterial adhesive carbohydrate polymer composed of galactose and phenylboronic acid. The objective was to facilitate sutureless wound closure by specially distinguishing between bacteria and nontarget cells and subsequently employing photothermal methods to eradicate the bacteria. AuNRs-PU demonstrated high photothermal conversion efficiency in 808 nm laser and effectively caused physical harm to drug-resistant P. aeruginosa. By integrating the multifunctional bacterial targeting copolymer onto AuNRs, AuNRs-PU showed rapid and efficient bacterial targeting and aggregation in the presence of bacteria and cells, consequently shielding cells from bacterial harm. In a diabetic rat wound model, AuNRs-PU played a crucial role in enhancing healing by markedly decreasing inflammation and expediting epidermis formation, collagen deposition, and neovascularization levels. Consequently, the multifunctional photothermal therapy shows promise in addressing the complexities associated with managing drug-resistant infected wound healing.

Exosome Loaded Protein Hydrogel for Enhanced Gelation Kinetics and Wound Healing.

Exosomes are being increasingly explored in biomedical research for wound healing applications. Exosomes can improve blood circulation and endocrine signaling, resulting in enhanced cell regeneration. However, exosome treatments suffer from low retention and bioavailability of exosomes at the wound site. Hydrogels are a popular tool for drug delivery due to their ability to encapsulate drugs in their network and allow for targeted release. Recently, hydrogels have proven to be an effective method to provide increased rates of wound healing when combined with exosomes that can be applied noninvasively. We have designed a series of single-domain protein-based hydrogels capable of physical cross-linking and upper critical solution temperature (UCST) behavior. Hydrogel variant Q5, previously designed with improved UCST behavior and a significantly enhanced gelation rate, is selected as a candidate for encapsulation release of exosomes dubbed Q5Exo. Q5Exo exhibits low critical gelation times and significant decreases in wound healing times in a diabetic mouse wound model showing promise as an exosome-based drug delivery tool and for future hybrid, noninvasive protein-exosome design.

Versatile conductive hydrogel orchestrating neuro–immune microenvironment for rapid diabetic wound healing through peripheral nerve regeneration

Diabetic wound (DW), notorious for prolonged healing processes due to the unregulated immune response, neuropathy, and persistent infection, poses a significant challenge to clinical management. Current strategies for treating DW primarily focus on alleviating the inflammatory milieu or promoting angiogenesis, while limited attention has been given to modulating the neuro-immune microenvironment. Thus, we present an electrically conductive hydrogel dressing and identify its neurogenesis influence in a nerve injury animal model initially by encouraging the proliferation and migration of Schwann cells. Further, endowed with the synergizing effect of near-infrared responsive release of curcumin and nature-inspired artificial heterogeneous melanin nanoparticles, it can harmonize the immune microenvironment by restoring the macrophage phenotype and scavenging excessive reactive oxygen species. This in-situ formed hydrogel also exhibits mild photothermal therapy antibacterial efficacy. In the infected DW model, this hydrogel effectively supports nerve regeneration and mitigates the immune microenvironment, thereby expediting the healing progress. The versatile hydrogel exhibits significant therapeutic potential for application in DW healing through fine-tuning the neuro-immune microenvironment.

An NIR-responsive hydrogel loaded with polydeoxyribonucleotide nano-vectors for enhanced chronic wound healing

Chronic diabetic wounds are difficult to treat due to imbalanced inflammatory responses, high blood glucose levels, and bacterial infections. Novel therapeutic approaches based on nucleic acid analogues have been proposed, with unique advantages in improving angiogenesis, increasing collagen synthesis, and exerting anti-inflammatory effects. However, the inherent electronegativity of nucleic acids makes them less susceptible to cellular uptake. In this paper, a kind of near infrared (NIR)-responsive nanocomposite hydrogel loaded with nucleic acid vectors was proposed for promoting wound healing. The redox system composed of molybdenum disulphide nanosheets (MoS2 NSs) initiated the copolymerization of quaternized chitosan containing double bonds and N-isopropylacrylamide (NIPAAm) to form the matrix. In addition, MoS2 NSs with photothermal conversion performance endow the nanocomposite hydrogel to have NIR-response property and act as physical crosslinking points in the matrix. Polydeoxyribonucleotides (PDRN), which have the effect of promoting wound healing, were made into nucleic acid vectors, and loaded into the NIR-responsive hydrogel. MoS2 NSs can convert NIR irradiation into heat, causing phase transitions of temperature-sensitive segments that trigger volume contraction of the hydrogel to extrude the nucleic acid vector. Promoting angiogenesis, slowing inflammation, and guiding tissue regeneration were demonstrated in the diabetic wound model treated with the NIR-responsive nanocomposite hydrogel.

Comparison of St. John's wort oil and thiocilline ointment on wound healing in a diabetic rat model

Aims: In diabetic patients, wound healing is impaired and wounds are often infected with multifactorial agents. This study aimed to compare the effectiveness of St. John’s wort and ointment containing bacitracin-neomycin (thiocilline) to improve wound healing in a diabetic infected wound model. Methods: Rats in which diabetes was induced by administering 60 mg/kg streptozotocin (STZ) were considered diabetic if their blood sugar levels were above 300 mg/dl 72 hours later. Group 1: Control (Non diabetic) group, Group 2: Diabetes group. During wound care, both groups were disinfected with povidone iodine (PI) and the right lumbar region of each rat was dressed with thiocilline and the left lumbar region was dressed with St. John’s wort oil. Considering the wound healing period, the study was terminated after an average of 20 days. In histopathological examination, ulceration, necrosis, epithelialization, congestion, edema, polymorphous nucleated leukocyte (PNL), monocyte, fibroblast, and neovascularization were evaluated. Results: In histopathological evaluation, there was a statistically significant decrease in ulceration and necrosis in the group treated with St. John’s wort oil compared to the group given thiocilline (p=0.04). In terms of epithelialization, there was a statistically significant increase in the group dressed with St. John’s wort oil compared to the group given thiocilline (p=0.03). There was a statistically significant decrease in congestion and edema in the group treated with St. John’s wort oil compared to the group given thiocilline (p=0.03). There was a statistically significant increase in fibroblast and neovascularization in the group treated with St. John’s wort oil compared to the group given thiocilline (p=0.02). Conclusion: Histopathologic ally, epithelialization, fibroblast, and neovascularization, which have important functions in the wound healing process, increased in diabetic rats administered St. John’s wort. Although it is used in traditional medicine due to its antidepressant effectiveness, we believe that St. John’s wort can be used in wounds that develop in diabetic patients, as it has the potential to increase the wound healing process.

Carbonized Polymer Dot-Tannic Acid Nanoglue: Tissue Reinforcement with Concurrent Fluorescent Tracking, Insulin Delivery, and Reactive Oxygen Species Regulation for Normal and Diabetic Wound Healing.

Nanotizing biosealant components offer a multitude of chemical functionalities for superior adhesion-cohesion, delivering unique properties for comprehensive wound healing that are otherwise impossible to achieve using commercial variants. For the first time, a two-step controlled hydrothermal pyrolysis is reported to nanotize dopamine, phloroglucinol, and glutaraldehyde into carbon dot (CD) to be subsequently converted into carbonized polymer dot (CPD) with gelatin as a co-substrate. Chemical crosslinking of CD with gelatin through Schiff base formation before the second pyrolysis step ensures a complex yet porous polymeric network. The retention of chemical functionalities indigenous to CD substrates and gelatin along with the preservation of CD photoluminescence in CPD for optical tracking is achieved. A unique nanoformulation is created with the CPD through tannic acid (TA) grafting evolving CPD-TA nanoglue demonstrating ≈1.32MPa strength in lap shear tests conducted on porcine skin, surpassing traditional bioadhesives. CPD-TA nanoglue uploaded insulin as chosen cargo disbursal at the wound site for healing normal and in vitro diabetic wound models using HEKa cells with extraordinary biocompatibility. Most importantly, CPD-TA can generate reactive oxygen species (ROS) and scavenge simultaneously under ambient conditions (23W white LED or dark) for on-demand sterilization or aiding wound recovery through ROS scavenging.

Hybrid biomaterial hydrogel loading iRGD&PS double modified lipid nanoparticles ameliorates diabetic wound healing through promoting efferocytosis and glycolysis-related macrophage reprogramming

Efferocytosis is a critical process whereby macrophages residing in the wound area play a key role in the efficient clearing and degradation of apoptotic neutrophils. This process is followed by a phenotypic transition toward an anti-inflammatory state, essential for inflammation resolution and tissue repair. The cystine/glutamate antiporter SLC7A11 has recently been identified as an inhibitor of efferocytosis, and its blockade has been found to enhance wound healing. In this study, we demonstrated that tiliroside, a plant-derived glycoside containing flavones, binds directly to SLC7A11 and pyruvate kinase isozyme M2 (PKM2). This was established by molecular docking predictions and activity-based protein profiling (ABPP). Cytological experiments revealed that tiliroside promoted the process of efferocytosis and led to glycolysis-related macrophage reprogramming. To facilitate targeted drug delivery to macrophages at diabetic wound sites, we designed a novel hybrid biomaterial. This hybrid biomaterial, prepared as Gel@Til iRGD&PS@PLGA NPs is manufactured by loading tiliroside (Til)-conjugated iRGD&PS double modified lipid nanoparticles (iRGD&PS@PLGA NPs) into a pH-responsive hydrogel matrix. The administration of Gel@Til iRGD&PS@PLGA NPs in diabetic cutaneous wound models has been shown to significantly promote tissue regeneration through the promotion of efferocytosis and glycolysis-related macrophage reprogramming. Therefore, this study introduces a novel approach to diabetic wound management by leveraging the promotion of efferocytosis.

Multifunctional Bioactive Nanozyme Systems for Enhanced Diabetic Wound Healing.

The protracted transition from inflammation to proliferation in diabetic wound healing poses significant challenges, exacerbated by persistent inflammatory responses and inadequate vascularization. To address these issues, a novel nanozymatic therapeutic approach utilizing asymmetrically structured MnO₂-Au-mSiO₂@aFGF Janus nanoparticles is engineered. Nanozymes featuring a mSiO₂ head and MnO₂ extensions, into which acidic fibroblast growth factor (aFGF) is encapsulated, resulting in MnO₂-Au-mSiO₂@aFGF Janus nanoparticles (mSAM@aFGF), are synthesized. This nanozyme system effectively emulates enzymatic activities of catalase (CAT) and superoxide dismutase (SOD), catalyzing degradation of reactive oxygen species (ROS) and generating oxygen. In addition, controlled release of aFGF fosters tissue regeneration and vascularization. In vitro studies demonstrate that mSAM@aFGF significantly alleviates oxidative stress in cells, and enhances cell proliferation, migration, and angiogenesis. An injectable hydrogel based on photocrosslinked hyaluronic acid (HAMA), incorporating the nanozymatic ROS-scavenging and growth factor-releasing system, is developed. The HAMA-mSAM@aFGF hydrogel exhibits multifaceted benefits in a diabetic wound model, including injectability, wound adhesion, hemostasis, anti-inflammatory effects, macrophage polarization from M1 to M2 phenotype, and promotion of vascularization. These attributes underscore the potential of this system to facilitate transition from chronic inflammation to the proliferative phase of wound repair, offering a promising therapeutic strategy for diabetic wound management.

Orientin promotes diabetic wounds healing by suppressing ferroptosis via activation of the Nrf2/GPX4 pathway.

Diabetic patients often experience delayed wound healing due to impaired functioning of human umbilical vein endothelial cells (HUVECs) under high glucose (HG) conditions. This is because HG conditions trigger uncontrolled lipid peroxidation, leading to iron-dependent ferroptosis, which is caused by glucolipotoxicity. However, natural flavonoid compound Orientin (Ori) possesses anti-inflammatory bioactive properties and is a promising treatment for a range of diseases. The current study aimed to investigate the function and mechanism of Ori in HG-mediated ferroptosis. A diabetic wound model was established in mice by intraperitoneal injection of streptozotocin (STZ), and HUVECs were cultured under HG to create an invitro diabetic environment. The results demonstrated that Ori inhibited HG-mediated ferroptosis, reducing levels of malondialdehyde (MDA), lipid peroxidation, and mitochondrial reactive oxygen species (mtROS), while increasing decreased levels of malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species, as well as increased levels of glutathione (GSH). Ori treatment also improved the wound expression of glutathione peroxidase 4 (GPX4) and angiogenesis markers, reversing the delayed wound healing caused by diabetes mellitus (DM). Additional investigations into the mechanism revealed that Ori may stimulate the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 signaling pathway. Silencing Nrf2 in HG-cultured HUVECs negated the beneficial impact mediated by Ori. By stimulating the Nrf2/GPX4 signaling pathway, Ori may expedite diabetic wound healing by decreasing ferroptosis.

Electrical Stimulating Redox Membrane Incorporated with PVA/Gelatin Nanofiber for Diabetic Wound Healing.

Chronic wounds adversely affect the quality of life. Although electrical stimulation has been utilized to treat chronic wounds, there are still limitations to practicing it due to the complicated power system. Herein, an electrostimulating membrane incorporated with electrospun nanofiber (M-sheet) to treat diabetic wounds is developed. Through the screen printing method, the various alternate patterns of both Zn and AgCl on a polyurethane substrate, generating redox-mediated electrical fields are introduced. The antibacterial ability of the patterned membrane against both E. coli and S. aureus is confirmed. Furthermore, the poly(vinyl alcohol) (PVA)/gelatin electrospun fiber is incorporated into the patterned membrane to enhance biocompatibility and maintain the wet condition in the wound environment. The M-sheet can improve cell proliferation and migration in vitro and has an immune regulatory effect by inducing the polarization of macrophage to the M2 phenotype. Finally, when applied to a diabetic skin wound model, the M-sheet displays an accelerated wound healing rate and enhances re-epithelialization, collagen synthesis, and angiogenesis. It suggests that the M-sheet is a simple and portable system for the spontaneous generation of electrical stimulation and has great potential to be used in the practical wound and other tissue engineering applications.

Multifunctional Microneedle Patch Based on Metal-Phenolic Network with Photothermal Antimicrobial, ROS Scavenging, Immunomodulatory, and Angiogenesis for Programmed Treatment of Diabetic Wound Healing.

In diabetic patients with skin injuries, bacterial proliferation, accumulation of reactive oxygen species (ROS) in the tissues, and impaired angiogenesis make wound healing difficult. Therefore, eliminating bacteria, removing ROS, and promoting angiogenesis are necessary for treating acute diabetic wounds. In this study, benefiting from the ability of polyphenols to form a metal-phenolic network (MPN) with metal ions, TA-Eu MPN nanoparticles (TM NPs) were synthesized. The prepared photothermal agent CuS NPs and TM NPs were then loaded onto the supporting base and needle tips of PVA/HA (PH) microneedles, respectively, to obtain PH/CuS/TM microneedles. Antibacterial experiments showed that microneedles loaded with CuS NPs could remove bacteria by the photothermal effect. In vitro experiments showed that the microneedles could effectively scavenge ROS, inhibit macrophage polarization to the M1 type, and induce polarization to the M2 type as well as have the ability to promote vascular endothelial cell migration and angiogenesis. Furthermore, in vivo experiments showed that PH/CuS/TM microneedles accelerated wound healing by inhibiting pro-inflammatory cytokines and promoting angiogenesis in a diabetic rat wound model. Therefore, PH/CuS/TM microneedles have efficient antibacterial, ROS scavenging, anti-inflammatory, immunomodulatory, and angiogenic abilities and hold promise as wound dressings for treating acute diabetic wounds.

Biohybrid Nanorobots Carrying Glycoengineered Extracellular Vesicles Promote Diabetic Wound Repair through Dual-Enhanced Cell and Tissue Penetration.

Considerable progress has been made in the development of drug delivery systems for diabetic wounds. However, underlying drawbacks, such as low delivery efficiency and poor tissue permeability, have rarely been addressed. In this study, a multifunctional biohybrid nanorobot platform comprising an artificial unit and several biological components is constructed. The artificial unit is a magnetically driven nanorobot surface modified with antibacterial 2-hydroxypropyltrimethyl ammonium chloride chitosan, which enables the entire platform to move and has excellent tissue penetration capacity. The biological components are two-step engineered extracellular vesicles that are first loaded with mangiferin, a natural polyphenolic compound with antioxidant properties, and then glycoengineered on the surface to enhance cellular uptake efficiency. As expected, the platform is more easily absorbed by endothelial cells and fibroblasts and exhibits outstanding dermal penetration performance and antioxidant properties. Encouraging results are also observed in infected diabetic wound models, showing improved wound re-epithelialization, collagen deposition, angiogenesis, and accelerated wound healing. Collectively, a biohybrid nanorobot platform that possesses the functionalities of both artificial units and biological components serves as an efficient delivery system to promote diabetic wound repair through dual-enhanced cell and tissue penetration and multistep interventions.