Diabetes mellitus is one of the most challenging epidemics facing the world today, with over 300 million patients affected worldwide. A significant complication associated with diabetes is hyperglycemia, which impairs wound healing. The rise in the diabetic patient population in recent years has precipitated an increase in the incidence and prevalence of chronic diabetic wounds, most commonly the diabetic foot ulcer. Although foot ulcers are difficult to treat due to their complicated pathology, outcomes have improved with the development of increasingly sophisticated biomaterials that accelerate healing. In this review, we describe recently developed biomaterials that elicit healing through cell-material interactions and/or the sustained delivery of drugs. These tunable therapeutic systems increase angiogenesis, collagen deposition, cell proliferation, and growth factors concentrations, while decreasing inflammation and enzymatic degradation of the extracellular matrix. As the field of biomaterials for wound healing continues to mature, we expect to witness a broader range of clinical options that will speed healing times and improve patient quality of life.

Hyperbaric oxygen (HBO) therapy has been used as an adjunctive therapy for diabetic foot ulcers, although its mechanism of action is not completely understood. Recently, it has been shown that HBO mobilizes the endothelial progenitor cells (EPCs) from bone marrow that eventually will aggregate in the wound. However, the gathering of the EPCs in diabetic wounds is impaired because of the decreased levels of local stromal-derived factor-1α (SDF-1α). Therefore, we investigated the influence of HBO on hypoxia-inducible factor 1 (HIF-1), which is a central regulator of SDF-1α and is down-regulated in diabetic wounds. The effects of HBO on HIF-1α function were studied in human dermal fibroblasts, SKRC7 cells, and HIF-1α knock-out and wild-type mouse embryonic fibroblasts using appropriate techniques (Western blot, quantitative polymerase chain reaction, and luciferase hypoxia-responsive element reporter assay). Cellular proliferation was assessed using H(3) -thymidine incorporation assay. The effect of HIF in combination with HBOT was tested by inoculating stable HIF-1α-expressing adenovirus (Adv-HIF) into experimental wounds in db/db mice exposed to HBO. HBO activates HIF-1α at several levels by increasing both HIF-1α stability (by a non-canonical mechanism) and activity (as shown both by induction of relevant target genes and by a specific reporter assay). HIF-1α induction has important biological relevance because the induction of fibroblast proliferation in HBO disappears when HIF-1α is knocked down. Moreover, the local transfer of stable HIF-1α-expressing adenovirus (Adv-HIF) into experimental wounds in diabetic (db/db mice) animals has an additive effect on HBO-mediated improvements in wound healing. In conclusion, HBO stabilizes and activates HIF-1, which contributes to increased cellular proliferation. In diabetic animals, the local transfer of active HIF further improves the effects of HBO on wound healing. © 2014 by the Wound Healing Society.

Diabetic wounds pose a significant challenge to public health, primarily due to insufficient blood vessel supply, bacterial infection, excessive oxidative stress, and impaired antioxidant defenses. The aforementioned condition not only places a significant physical burden on patients' prognosis, but also amplifies the economic strain on the medical system in treating diabetic wounds. Currently, the effectiveness of available treatments for diabetic wounds is limited. However, there is hope in the potential of metal nanoparticles (MNPs) to address these issues. MNPs exhibit excellent anti-inflammatory, antioxidant, antibacterial and pro-angiogenic properties, making them a promising solution for diabetic wounds. In addition, MNPs stimulate the expression of proteins that promote wound healing and serve as drug delivery systems for small-molecule drugs. By combining MNPs with other biomaterials such as hydrogels and chitosan, novel dressings can be developed and revolutionize the treatment of diabetic wounds. The present article provides a comprehensive overview of the research progress on the utilization of MNPs for treating diabetic wounds. Building upon this foundation, we summarize the underlying mechanisms involved in diabetic wound healing and discuss the potential application of MNPs as biomaterials for drug delivery. Furthermore, we provide an extensive analysis and discussion on the clinical implementation of dressings, while also highlighting future prospects for utilizing MNPs in diabetic wound management. In conclusion, MNPs represent a promising strategy for the treatment of diabetic wound healing. Future directions include combining other biological nanomaterials to synthesize new biological dressings or utilizing the other physicochemical properties of MNPs to promote wound healing. Synthetic biomaterials that contain MNPs not only play a role in all stages of diabetic wound healing, but also provide a stable physiological environment for the wound-healing process.© 2024 Zheng et al.

A previous experiment using an in vivo mouse model has proved that hypoxia increased angiogenesis during wound healing. It was hypothesised that one of the mechanisms for wound healing impairment in diabetes includes insufficient angiogenic ability in response to hypoxia. The current study aims to investigate the influence of hypoxia on wound healing in diabetic mice. Oxygen-impermeable (hypoxic group) and -permeable membranes (normoxic group) were used to control topical oxygen tension. Membranes were applied to symmetrical excisional wounds on diabetic mice. Wound area, granulated tissue thickness, and vascular density were analyzed. As results, a decrease in wound size on day 7 was observed in the normoxic group (20.7 ± 3.64%) compared with the hypoxic group (34.1 ± 4.98%). The normoxic group also showed significantly thicker granulated tissue than the hypoxic group (225.7 ± 54.7 vs 128.7 ± 42.4 µm). There was no significant difference in mean vascular density between normoxic and hypoxic groups (0.046 ± 0.022 vs 0.038 ± 0.017 mm(2)/mm(2), p = 0.80). Contrary to healthy mice, diabetic mice have shown no enhancement of angiogenesis in hypoxic condition. The findings illustrate that neovascularisation in response to hypoxia is diminished in diabetic wounds.

Impaired diabetic wound healing represents a devastating and rapidly growing clinical problem associated with high morbidity, mortality, and recurrence rates. Engineering therapeutic angiogenesis in the wounded tissue is critical for successful wound healing. However, stimulating functional angiogenesis of the diabetic wound remains a great challenge, due to the oxidative damage and denaturation of bio-macromolecule-based angiogenic agents in the oxidative diabetic wound microenvironment. Here, we present a unique "seed-and-soil" strategy that circumvents the limitation by simultaneously reshaping the oxidative wound microenvironment into a proregenerative one (the "soil") and providing proangiogenic miRNA cues (the "seed") using an miRNA-impregnated, redox-modulatory ceria nanozyme-reinforced self-protecting hydrogel (PCN-miR/Col). The PCN-miR/Col not only reshapes the hostile oxidative wound microenvironment, but also ensures the structural integrity of the encapsulated proangiogenic miRNA in the oxidative microenvironment. Diabetic wounds treated with the PCN-miR/Col demonstrate a remarkably accelerated wound closure and enhanced quality of the healed wound as featured by highly ordered alignment of collagen fiber, skin appendage morphogenesis, functional new blood vessel growth, and oxygen saturation.

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Diabetes mellitus is a costly disease and nearly one-third of these costs are attributed to management of diabetic foot disease including chronic, non-healing, diabetic foot ulcers. Therefore, much effort has been placed into understanding the pathogenesis of diabetic wounds and novel therapeutics. A relatively new area of interest has been macrophage polarization and its role in diabetic wound healing. Diabetic wounds show dysregulated and persistent M1 (pro-inflammatory) macrophage polarization whereas normal wounds will display a transition to M2 (pro-healing) macrophages around day three after wounding. We reviewed factors known to affect macrophage polarization, mostly focused on those that contribute to M2 macrophage polarization, and potential treatments that at least in part target macrophage polarization in the diabetic wound bed. Much of the work has been aimed at reducing hyperglycemia and encouraging pro-inflammatory cytokine neutralization or decreased expression given this has a significant role in producing M1 macrophages. Treatment of diabetic wounds will likely require a multi-modal approach including management of underlying diabetes and control of hyperglycemia, topical therapeutics, and prevention of secondary infection and inflammation.Copyright © 2021. Published by Elsevier Inc.

Diabetic chronic wound, characterized by prolonged inflammation and impaired angiogenesis, has become one of the most serious challenges in clinic and pose a significant healthcare burden worldwide. Although a great variety of wound dressings have been developed, few of encouraged achievements were obtained so far. In this study, the gene-activated strategy was applied to enhance sustained expression of vascular endothelial growth factor (VEGF) and achieve better healing outcomes by regulating inflammation and promoting angiogenesis. The gene-activated bilayer dermal equivalents (Ga-BDEs), which has good biocompatibility, were fabricated by loading the nano-sized complexes of Lipofectamine 2000/plasmid DNA-encoding VEGF into a collagen-chitosan scaffold/silicone membrane bilayer dermal equivalent. The DNA complexes were released in a sustained manner and showed the effective transfection capacities to up-regulate the expression of VEGF in vitro. To overcome cutaneous contraction of rodents and mimic the wound healing mechanisms of the human, a reformative rat model of full-thickness diabetic chronic wound was adopted. Under the treatment of Ga-BDEs, speeding wound healing was observed, which is accompanied by the accelerated infiltration and phenotype shift of macrophages and enhanced angiogenesis in early and late healing phases, respectively. These proved that Ga-BDEs possess the functions of immunomodulation and pro-angiogenesis simultaneously. Subsequently, the better regeneration outcomes, including deposition of oriented collagen and fast reepithelialization, were achieved. All these results indicated that, being different from traditional pro-angiogenic concept, the up-regulated expression of VEGF by Ga-BDEs in a sustained manner shows versatile potentials for promoting the healing of diabetic chronic wounds.© 2020 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

Metal oxide nanoparticles present stable and unique performance that makes them suitable for various biomedical applications. There are four common exposure ways that nanoparticles enter our body: injection, inhalation, skin penetration, and ingestion. Among them, injection, ingestion, and skin routes may become significant ways for nano-scale treatment and cosmetics, and inhalation is the essential way for occupational exposure. All those nanoparticles could pass through the exposure routes and enter the circulation, which could cause damage on the cardiovascular system. So it is necessary to evaluate the toxicity of metal oxide nanoparticles and to explore the mechanism. This review chose four commonly used nanometal oxides to discuss about the toxicity they produced, the function they affected, and the mechanisms on cardiovascular endothelial cells. First, we discussed the toxicity they caused. These nanoparticles are less toxic when applied in low doses, but owing to the small particle size and large specific surface area, acute exposure or the metal ions released by nanoparticles will lead to phenotypic changes of endothelial cells, oxidative stress, and apoptosis. An endothelial cell is an essential part of blood vessels and could act as a barrier, maintain vascular tension, and keep the balance between coagulation and anticoagulation. Once vascular endothelium is injured or exposed to vascular risk factors, it would cause endothelial activation, endothelial dysfunction, and nitric oxide (NO) synthase (NOS) dysfunction, which are closely related to the cardiovascular disease. Finally, we talked about the mechanisms by four levels, and we especially mentioned inflammation, the production of reactive oxygen species, and NO.© 2020 John Wiley & Sons, Ltd.

This study was carried out to compare the efficacy of silver nanoparticle gel (SG), nanosilver foam (SF) and collagen (C) dressings in partial thickness burn wounds.This was a single-center, prospective cohort study carried out over a period of 1 year on patients with 15-40% partial thickness thermal burns ≤48 h. Each patient received all three dressings (silver-nanoparticle gel, nanosilver foam, collagen) simultaneously at 3 randomly selected areas which were comparable in terms of burn depth and surface area. Efficacy of the dressings was assessed in terms of healing rates, time taken and ease of application, pain at dressing change, cost, wound-swab culture and scar quality (at 3 months).A total of 20 patients were included. In SF group, number of patients with 60%-80% re-epithelialization on day10 (SG: 10/20; C: 10/20; SF: 16/20; p = 0.042) and complete healing on day14 (SF: 11/20, C: 6/20, SG: 4/20; p = 0.032) was significantly higher. The time for dressing change was similar at admission (p = 0.918) and day 10 (p = 0.163), although majority of the patients in SF group needed less than 10 min. The time taken (<10 min) was significantly lower in SF group by 14th day (SF: 18/20 C: 6/20 SG: 6/20; p < 0.001). The ease of application rated by clinicians as "extremely easy" was significantly better in SF group (SG: 78%, C: 80%, SF: 95%; p = 0.011). There was a significantly faster decrease in pain scores in SF group by 5th day (VAS score SF: 6, C: 8; SG: 8; p = 0.038), however, pain scores were comparable at 2 weeks. The scar quality (p = 0.82), cost (p = 0.09) and infection rates (SG: 7/20; C: 4/20; SF: 3/20; p = 0.05) were comparable. The need for skin-graft cover was lower in SF group (SG: 5/20; C: 3/20; SF: 1/20).Nanosilver-foam dressings were found to be more efficacious for re-epithelialization, healing, ease of application, tolerance when compared to silver nanoparticle gel and collagen dressings in partial-thickness burns. All were found to be safe.Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.

Worldwide water contamination treatment and water security are essential for all living organisms. Among various water contaminants, dye, and bacteria pollution needs to be solved urgently.In this work, a ceramic sheet from monodisperse, porous silica nanospheres (SiO NSs) with an average diameter of 220 was prepared. The prepared SiO ceramic sheets were investigated as a "filtration" material in removing dyes (alcian blue, AB; and methylene blue, MB) and bacteria (). The obtained sheets had efficient adsorption efficiency of 98.72% (for AB) and 97.35% (for MB), and a high adsorption capacity for AB is 220 (mg/g), for MB is 176 (mg/g). Furthermore, these SiO ceramic sheets had a high recycling capability for removing dyes by calcination. Being modified by Ag nanoclusters, the ceramic sheets present a strong bactericidal function.Our results demonstrated that the obtained SiO non-sintered ceramic sheets is rapid and efficient in the filtration of dyes and bacteria from polluted water.© 2021 Ren et al.

Silver nanoparticles (AgNPs) have been one of the most attractive nanomaterials in biomedicine due to their unique physicochemical properties. In this paper, we review the state-of-the-art advances of AgNPs in the synthesis methods, medical applications and biosafety of AgNPs. The synthesis methods of AgNPs include physical, chemical and biological routes. AgNPs are mainly used for antimicrobial and anticancer therapy, and also applied in the promotion of wound repair and bone healing, or as the vaccine adjuvant, anti-diabetic agent and biosensors. This review also summarizes the biological action mechanisms of AgNPs, which mainly involve the release of silver ions (Ag), generation of reactive oxygen species (ROS), destruction of membrane structure. Despite these therapeutic benefits, their biological safety problems such as potential toxicity on cells, tissue, and organs should be paid enough attention. Besides, we briefly introduce a new type of Ag particles smaller than AgNPs, silver Ångstrom (Å, 1 Å = 0.1 nm) particles (AgÅPs), which exhibit better biological activity and lower toxicity compared with AgNPs. Finally, we conclude the current challenges and point out the future development direction of AgNPs.© The author(s).

Antimicrobial materials with immobilized/entrapped silver nanoparticles (AgNPs) are of considerable interest. There is significant debate on the mode of bactericidal action of AgNPs, and both contact killing and/or ion mediated killing have been proposed. In this study, AgNPs were immobilized on an amine-functionalized silica surface and their bactericidal activity was studied concurrently with the silver release profile over time. This was compared with similar studies performed using colloidal AgNPs and AgCl surfaces that released Ag ions. We conclude that contact killing is the predominant bactericidal mechanism and surface immobilized nanoparticles show greater efficacy than colloidal AgNPs, as well as a higher concentration of silver ions in solution. In addition, the AgNP immobilized substrate was used multiple times with good efficacy, indicating this immobilization protocol is effective for retaining AgNPs while maintaining their disinfection potential. The antibacterial surface was found to be extremely stable in aqueous medium and no significant leaching (∼1.15% of total silver deposited) of the AgNPs was observed. Thus, immobilization of AgNPs on a surface may promote reuse, reduce environmental risks associated with leaching of AgNPs and enhance cost effectiveness.

Resistance to silver compounds as determined by bacterial plasmids and genes has been defined by molecular genetics. Silver resistance conferred by the Salmonella plasmid pMGH100 involves nine genes in three transcription units. A sensor/responder (SilRS) two-component transcriptional regulatory system governs synthesis of a periplasmic Ag(I)-binding protein (SilE) and two efflux pumps (a P-type ATPase (SilP) plus a three-protein chemiosmotic RND Ag(I)/H+ exchange system (SilCBA)). The same genes were identified on five of 19 additional IncH incompatibility class plasmids but thus far not on other plasmids. Of 70 random enteric isolates from a local hospital, isolates from catheters and other Ag-exposed sites, and total genomes of enteric bacteria, 10 have recognizable sil genes. The centrally located six genes are found and functional in the chromosome of Escherichia coli K-12, and also occur on the genome of E. coli O157:H7. The use of molecular epidemiological tools will establish the range and diversity of such resistance systems in clinical and non-clinical sources. Silver compounds are used widely as effective antimicrobial agents to combat pathogens (bacteria, viruses and eukaryotic microorganisms) in the clinic and for public health hygiene. Silver cations (Ag+) are microcidal at low concentrations and used to treat burns, wounds and ulcers. Ag is used to coat catheters to retard microbial biofilm development. Ag is used in hygiene products including face creams, "alternative medicine" health supplements, supermarket products for washing vegetables, and water filtration cartridges. Ag is generally without adverse effects for humans, and argyria (irreversible discoloration of the skin resulting from subepithelial silver deposits) is rare and mostly of cosmetic concern.

Patients with diabetic wounds have deficient local and systemic cellular immunity. Herein, a new silver nanoparticle-containing hydrogel with antifouling properties was developed for enhancing the immune response in diabetic wound healing. The antifouling property was obtained by adjusting the composition of cationic chitosan and anionic dextran to approach zero charge. Furthermore, this hybrid hydrogel showed long-lasting and broad-spectrum antibacterial activity. Rapid wound contraction was observed after the treatment with the hydrogel, which suggested its superior healing activity to promote fibroblast migration, granulation tissue formation, and angiogenesis. The upregulation of CD68+ and CD3+ expression levels demonstrated that the hydrogel could trigger immune responses in the treatment of wound healing. These results show that this antifouling hybrid hydrogel as a wound dressing provided a promising strategy for the treatment of diabetic ulcers.

Impaired wound healing is a major complication. A few factors such as blood glucose level, poor circulation, immune system deficiency, and infection are the root causes of impaired wound healing. The aim of the present study was to bio-synthesize copper nanoparticles with potential antibacterial activity against wound-associated pathogens.Copper nanoparticles were fabricated using the sol-gel method with the mixing of leaf extract in metal salt solution. The particles were then later characterized using UV spectroscopy, SEM, TEM, FTIR, and XRD, and evaluated for their antibacterial activity and its MIC against four wound-associated pathogens.The results obtained from TEM, SEM, and XRD characterization showed that the particle size was below 100 nm and of spherical shape. FTIR analysis showed the possibility of various biomolecules, which have a role in capping and stabilizing copper nanoparticles. The particles synthesized showed antibacterial activity against four wound-associated pathogens, and ).The biosynthesized copper nanoparticles showed potent antimicrobial activity, thus the antibacterial activity of the synthesized copper nanoparticles could be used in several biomedical applications. Additionally, they can be exploited as a better therapeutic agent for treating infection seen in impaired diabetic wounds. The particles synthesized by the biological route are eco-friendly, less toxic, feasible, and cost effective.©Copyright 2018 Turk J Pharm Sci, Published by Galenos Publishing House.

The complex hyperglycemic, hypoxic, and reactive oxygen species microenvironment of diabetic wound leads to vascular defects and bacterial growth and current treatment options are relatively limited by their poor efficacy.Herein, a functional molecule-mediated copper ions co-assembled strategy was constructed for collaborative treatment of diabetic wounds. Firstly, a functional small molecule 2,5-dimercaptoterephthalic acid (DCA) which has symmetrical carboxyl and sulfhydryl structure, was selected for the first time to assisted co-assembly of copper ions to produce multifunctional nanozymes (Cu-DCA NZs). Secondly, the Cu-DCA NZs have excellent multicatalytic activity, and photothermal response under 808 nm irradiation. In vitro and in vivo experiments showed that it not only could efficiently inhibit bacterial growth though photothermal therapy, but also could catalyze the conversion of intracellular hydrogen peroxide to oxygen which relieves wound hypoxia and improving inflammatory accumulation. More importantly, the slow release of copper ions could accelerate cellular proliferation, migration and angiogenesis, synergistically promote the healing of diabetic wound furtherly.The above results indicate that this multifunctional nanozymes Cu-DCA NZs may be a potential nanotherapeutic strategy for diabetic wound healing.© 2023. BioMed Central Ltd., part of Springer Nature.

Copper possesses efficacy in wound healing which is a complex phenomenon involving various cells, cytokines and growth factors. Copper nanoparticles modulate cells, cytokines and growth factors involved in wound healing in a better way than copper ions. Chitosan has been shown to be beneficial in healing because of its antibacterial, antifungal, biocompatible and biodegradable polymeric nature. In the present study, chitosan-based copper nanocomposite (CCNC) was prepared by mixing chitosan and copper nanoparticles. CCNC was applied topically to evaluate its wound healing potential and to study its effects on some important components of healing process in open excision wound model in adult Wistar rats. Significant increase in wound contraction was observed in the CCNC-treated rats. The up-regulation of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1(TGF-β1) by CCNC-treatment revealed its role in facilitating angiogenesis, fibroblast proliferation and collagen deposition. The tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were significantly decreased and increased, respectively, in CCNC-treated rats. Histological evaluation showed more fibroblast proliferation, collagen deposition and intact re-epithelialization in CCNC-treated rats. Immunohistochemistry of CD31 revealed marked increase in angiogenesis. Thus, we concluded that chitosan-based copper nanocomposite efficiently enhanced cutaneous wound healing by modulation of various cells, cytokines and growth factors during different phases of healing process. Copyright © 2014 Elsevier B.V. All rights reserved.

Bacterial invasion, protracted inflammation, and angiogenesis inhibition are hallmarks of chronic diabetic wounds, bringing about patient morbidity and rising healthcare costs. For such wounds, there are currently few efficient therapies available.We reported the development of carboxymethyl chitosan (CMCS)-based self-healing hydrogel loaded with ultra-small copper nanoparticles (Cunps) for local treatment of diabetic wound healing. The structure of Cunps was identified by XRD, TEM, XPS and other methods, and the characterization of the synthesized Cunps-loaded self-healing carboxymethyl chitosan (CMCS)-protocatechualdehyde (PCA) hydrogel (Cunps@CMCS-PCA hydrogel) was further investigated. The therapeutic effect of Cunps@CMCS-PCA hydrogel in diabetic wound healing was explored in vitro and in vivo.The findings showed that a kind of ultra-small size copper nanoparticles with excellent biocompatibility was prepared. CMCS was chemically conjugated to PCA to form self-healing hydrogels via the formation of an amide bond followed by the loading of ultra-small copper nanoparticles. The obtained Cunps@CMCS-PCA hydrogel showed a typical three-dimensional interlinked network structure with self-healing ability and porosity. It exhibited good biocompatibility in diabetic wounds. Furthermore, Cunps@CMCS-PCA hydrogel group significantly prevented bacterial growth in the skin wound of diabetic rats as compared to model group and CMCS-PCA hydrogel-treated group. After 3 days, no visible bacterial proliferation was observed. It also increased angiogenesis through Cunps mediated activation of ATP7A to prevent induction of autophagy. Furthermore, Cunps@CMCS-PCA hydrogel mainly depended on PCA-induced inhibition on inflammation of macrophage via JAK2/STAT3 signaling pathway. As a result, compared with delayed wound healing process with lower wound healing rate valued at 68.6% within 7 days in the model group, Cunps@CMCS-PCA significantly accelerated wound healing recovery and increased wound healing rate to 86.5%, suggesting that Cunps@CMCS-PCA hydrogel effectively accelerated wound healing.Cunps@CMCS-PCA hydrogel offered a new therapeutic approach for quickening diabetic wound healing.© 2023 Geng et al.

Chronic non-healing diabetic wounds and ulcers can be fatal, lead to amputations, and remain a major challenge to medical, and health care sectors. Susceptibility to infection and impaired angiogenesis are two central reasons for the clinical consequences associated with chronic non-healing diabetic wounds. Herein, we successfully developed calcium ion (Ca) cross-linked sodium alginate (SA) hydrogels with both pro-angiogenesis and antibacterial properties. Our results demonstrated that deferoxamine (DFO) and copper nanoparticles (Cu-NPs) worked synergistically to enhance the proliferation, migration, and angiogenesis of human umbilical venous endothelial cells in vitro. Results of colony formation assay indicated Cu-NPs were effective against E. coli and S. aureus in a dose-dependent manner in vitro. An SA hydrogel containing both DFO and Cu-NPs (SA-DFO/Cu) was prepared using a Ca cross-linking method. Cytotoxicity assay and colony formation assay indicated that the hydrogel exhibited beneficial biocompatible and antibacterial properties in vitro. Furthermore, SA-DFO/Cu significantly accelerated diabetic wound healing, improved angiogenesis and reduced long-lasting inflammation in a mouse model of diabetic wound. Mechanistically, DFO and Cu-NPs synergistically stimulated the levels of hypoxia-inducible factor 1α and vascular endothelial growth factor in vivo. Given the pro-angiogenesis, antibacterial and healing properties, the hydrogel possesses high potential for clinical application in refractory wounds.Copyright © 2022. Published by Elsevier B.V.

Metal-organic frameworks (MOFs), a class of hybrid materials formed by the self-assembly of polydentate bridging ligands and metal-connecting points, have been studied for a variety of applications. Recently, these materials have been scaled down to nanometer sizes, and this Account details the development of nanoscale metal-organic frameworks (NMOFs) for biomedical applications. NMOFs possess several potential advantages over conventional nanomedicines such as their structural and chemical diversity, their high loading capacity, and their intrinsic biodegradability. Under relatively mild conditions, NMOFs can be obtained as either crystalline or amorphous materials. The particle composition, size, and morphology can be easily tuned to optimize the final particle properties. Researchers have employed two general strategies to deliver active agents using NMOFs: by incorporating active agents into the frameworks or by loading active agents into the pores and channels of the NMOFs. The modification of NMOF surfaces with either silica coatings or organic polymers improves NMOF stability, fine-tunes their properties, and imparts additional functionality. Preliminary biomedical applications of NMOFs have focused on their use as delivery vehicles for imaging contrast agents and molecular therapeutics. Because NMOFs can carry large amounts of paramagnetic metal ions, they have been extensively explored as magnetic resonance imaging (MRI) contrast agents. Both Gd(3+)- and Mn(2+)-containing NMOFs have shown excellent efficacy as T(1)-weighted contrast agents with large per metal- and per particle-based MR relaxivities. Fe(3+)-containing NMOFs have demonstrated excellent T(2)-weighted contrast enhancement. Upon intravenous injection of iron carboxylate NMOFs in Wistar rats, researchers observed negative signal enhancement in the liver and spleen, which dissipated over time, indicating the degradation and clearance of the NMOF. Through the incorporation of luminescent or high Z element building blocks, NMOFs have also served as viable contrast agents for optical imaging or X-ray computed tomography (CT) imaging. Incorporation of membrane impermeable dyes into NMOFs allowed for their uptake by cancer cells and for their controlled release as the framework decomposed. NMOFs have been used to deliver anticancer drugs and other chemotherapeutics. Cisplatin prodrugs were incorporated within NMOFs at exceptionally high levels, either through use of the prodrug as the building block or through attachment of the prodrug onto the framework after synthesis. These NMOFs were encapsulated within a silica shell and targeted to cancer cells. In vitro assays revealed that the targeted NMOFs possessed similar efficacy to cisplatin, while the nontargeted NMOFs were less active. Several different therapeutic molecules were loaded within porous iron-carboxylate NMOFs at unprecedented levels. The NMOF showed sustained drug release with no burst effect, and in vitro assays revealed that the nanoencapsulated drug possessed similar efficacy to the free drug. Although still at a very early stage of development, NMOFs have already shown great promise as a novel platform for nanomedicine. The compositional tunability and mild synthetic conditions used to produce NMOFs should allow for the incorporation of other imaging and therapeutic agents and their effective delivery to targeted cells in vivo.

Upon inflammation, neutrophils and subsequently monocytes infiltrate into the involved site. Neutrophils perform functions such as bacterial killing or tissue destruction and then undergo apoptosis, whereas monocytes differentiate into macrophages at the site. Macrophages and other phagocytes finally clear apoptotic neutrophils, leading to resolution of the inflammation. One of the key steps during inflammation is leukocyte infiltration, which is controlled chiefly by chemokines for neutrophils and monocytes. The production of these chemokines is regulated positively or negatively by iNOS-derived NO. Although the mechanisms underlying such dual effects of NO remain unknown, the level of NO and duration of NO exposure appear to be determining factors. The clearance of apoptotic neutrophils without causing further proinflammatory responses, on the other hand, is another key event during inflammation. The production of proinflammatory cytokines appears to be actively suppressed by TGF-β and NO, which are produced by phagocytes upon interaction with apoptotic cells. Overall, NO plays a critical role during inflammation and therefore, remains a potential target for developing therapeutics for inflammatory diseases.

The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-organic framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu release, thus enabling the direct application of Cu-MOF NPs to wounds.

Streptococcus agalactiae and Staphylococcus aureus are two pathogenetic agents of several infective diseases in humans. Biocidal effects and cellular internalization of ZnO nanoparticles (NPs) on two bacteria are reported, and ZnO NPs have a good bacteriostasis effect. ZnO NPs were synthesized in the EG aqueous system through the hydrolysis of ionic Zn2+ salts. Particle size and shape were controlled by the addition of the various surfactants. Bactericidal tests were performed in an ordinary broth medium on solid agar plates and in liquid systems with different concentrations of ZnO NPs. The biocidal action of ZnO materials was studied by transmission electron microscopy of bacteria ultrathin sections. The results confirmed that bactericidal cells were damaged after ZnO NPs contacted with them, showing both gram-negative membrane and gram-positive membrane disorganization. The surface modification of ZnO NPs causes an increase in membrane permeability and the cellular internalization of these NPs whereas there is a ZnO NP structure change inside the cells.

Thermoresponsive gels containing gold nanoparticles (AuNPs) were prepared using Pluronic (R) 127 alone (F1) and with hydroxypropyl methylcellulose (F2) at ratios of 15% w/w and 15: 1% w/w, respectively. AuNPs were evaluated for particle size, zeta-potential, polydispersity index (PDI), morphology and XRD pattern. AuNP-containing thermoresponsive gels were investigated for their gelation temperature, gel strength, bio-adhesive force, viscosity, drug content, in vitro release and exvivo permeation, in addition to in vitro antibacterial activity against bacteria found in burn infections, Staphylococcus aureus. In vivo burn healing and antibacterial activities were also investigated and compared with those of a commercial product using burn-induced infected wounds in mice. Spherical AuNPs sized 28.9-37.65 nm displayed a surface plasmon resonance band at 522 nm, a PDI of 0.461, and a zeta potential of 34.8 mV with a negative surface charge. F1 and F2 showed gelation temperatures of 37.2 degrees C and 32.3 degrees C, bio-adhesive forces of 2.45 +/- 0.52 and 4.76 +/- 0.84 dyne/cm(2), viscosities of 10,165 +/- 1.54 and 14,213 +/- 2.31 cP, and gel strengths between 7.4 and 10.3 sec, respectively. The in vitro release values of F1 and F2 were 100% and 98.03% after 6 h, with permeation flux values of (J1) 0.2974 +/- 2.85 and (J2) 0.2649 +/- 1.43 (mu g/cm(2).h), respectively. The formulations showed antibacterial activity with the highest values for wound healing properties, as shown in vivo and by histopathological studies. This study demonstrates that a smart AuNPs thermoresponsive gel was successful as an antibacterial and wound healing transdermal drug delivery system.

In this study we have reported an efficient antibacterial hybrid fabricated through surface functionalization of lysozyme capped gold nanoclusters (AUNC-L) with beta-lactam antibiotic ampicillin (AUNC-L-Amp). The prepared hybrid not only reverted the MRSA resistance towards ampicillin but also demonstrated enhanced antibacterial activity against non-resistant bacterial strains. Most importantly, upon awakening through cis-2-decenoic acid (cis-DA) exposure, the MRSA persister got inhibited by the AUNC-L-Amp treatment. Intraperitoneal administration of this hybrid eliminates the systemic MRSA infection in a murine animal model. Topical application of this nano conjugate eradicated MRSA infection from difficult to treat diabetic wound of rat and accelerated the healing process. Due to inherent bio-safe nature of gold, AUNC-L alone or in the construct (AUNC-L-Amp) demonstrated excellent biocompatibility and did not indicate any deleterious effects in in vivo settings. We postulate that AUNC-L-Amp overcomes the elevated levels of beta-lactamase at the site of MRSA antibiotic interaction with subsequent multivalent binding to the bacterial surface and enhanced permeation. Coordinated action of AUNC-L-Amp components precludes MRSA to attain resistance against the hybrid. We proposed that the inhibitory effect of AUNC-L-Amp against MRSA and its persister form is due to increased Amp concentration at the site of action, multivalent presentation and enhanced permeation of Amp through lysozyme-mediated cell wall lysis.

We report a new approach to selectively deliver antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan-modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes "see" bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillin-resistant Staphylococcus aureus (MRSA) as a model bacterium and vancomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vancomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vancomycin-loaded liposomes (without nanoparticle stabilizers) and free vancomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe, and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins.

Impaired angiogenesis and bacterial infection have increasingly been implicated as the major causes of delayed diabetic wound healing. However, there is currently no effective therapy. Here, we optimized a novel gene delivery system based on antimicrobial peptide (LL37) grafted ultra-small gold nanoparticles (AuNPs@LL37, ∼7 nm) for the topical treatment of diabetic wounds with or without bacterial infection. AuNPs@LL37 combines the advantages of cationic AuNPs that condense DNA with those of antibacterial peptides, which are both highly antibacterial and essential for enhancing cellular and nucleus entry to achieve high gene delivery efficiency. AuNPs@LL37 combined with pro-angiogenic (VEGF) plasmids (AuNPs@LL37/pDNAs) significantly improved the gene transfection efficiency in keratinocytes compared with pristine AuNPs/pDNAs, and showed similar expression to Lipo2000/pDNAs (a well-known highly efficient gene transfection agent). Moreover, our therapeutic depot showed higher antibacterial ability than the free antimicrobial peptides and the cationic AuNPs alone in vitro and in vivo due to synergistic effects. Furthermore, the combined system promoted angiogenesis and inhibited bacterial infection in diabetic wounds, resulting in accelerated wound closure rates, faster re-epithelization, improved granulation tissue formation and high VEGF expression. Finally, our therapeutic depot was highly biocompatible in vitro and in vivo, suggesting its potential as a feasible way to treat chronic diabetic wounds.

Persistent Infections and inflammation are associated with impaired wound healing in diabetic patients. There is a pressing demand for innovative antimicrobial strategies to address infections arising from antibiotic-resistant bacteria. Polymer-modified gold nanoparticles (AuNPs) show broad-spectrum antibacterial properties and significant biocompatibility. This study investigated the antibacterial and wound healing efficacy of hydrogel dressings conjugated with chitosan-AuNPs in diabetic model rats.Chitosan (CS)-functionalized gold nanoparticles (CS-AuNPs) were incorporated into hydrogel dressings (Gel/CS-AuNPs), which were formulated through the chemical cross-linking of gelatin with sodium alginate (SA). The basic characteristics of Gel/CS-AuNPs were analyzed by TEM, SEM, XRD, and UV-visible spectra. Rheological, swelling, degradation, and adhesive properties of Gel/CS-AuNPs were also determined. In vitro anti-bactericidal effects of the Gel/CS-AuNPs were analyzed with, and. In vitro biocompatibility of the Gel/CS-AuNPs was evaluated using NIH3T3 cells. The in vivo antibacterial and wound healing efficacy of the Gel/CS-AuNPs was analyzed in the diabetic wound model rats. Histological and immunofluorescence staining were performed to determine the status of angiogenesis, epithelization, inflammation response, and collagen deposition.Gel/CS-AuNPs demonstrated significant high biodegradability, water absorption bactericidal, and biocompatibility, and slight adhesiveness. Gel/CS-AuNPs exhibited pronounced antibacterial efficacy against gram-negative, gram-positive, and in a CS-AuNPs-dose-dependent manner. In the diabetic wound model rats, Gel/CS-AuNPs effectively killed, reduced inflammation, and promoted angiogenesis and collagen deposition and remodeling at the wound site. As a result, Gel/CS-AuNPs expedited the recovery process for infected diabetic wounds. Among the hydrogels with different CS-AuNPs concentrations, Gel/CS-Au with 25% CS-AuNPs showed the best bactericidal and wound healing performance.Gel/CS-AuNPs significantly improve the healing of -infected diabetic wounds in the rat model. Therefore, Gel/CS-AuNPs show great promise for the treatment of diabetic infection wound healing.© 2024 Meng et al.