Wound Infection Model Research Articles

Adipose-derived Stem Cells Improving Inflammatory and Proliferative Responses in an Infected and Ischemic Ulcer Model in Type 1 Diabetic Rats: Insights Into Bacterial Count, Stereological Parameters, microRNA-21, and FGF2 Regulation

Background: Adipose-derived stem cells (ADSCs) have been shown to enhance wound healing in rats with type 1 diabetes (DM1). Objectives: This experimental study aimed to explore how ADSC administration affects bacterial count, wound size, biomechanical and stereological parameters, and the expression of microRNA-21 and FGF2 in a rat model of infected, ischemic, and delayed wound healing in DM1. Methods: Twenty-four male adult Wistar rats weighing less than 250 g were randomly assigned to four groups (n = 6 per group). Type 1 diabetes was induced in all animals, resulting in the development of a delayed, ischemic, and infected wound model. The CGday4 and CGday8 groups served as controls. In the AGday4 group, the animals received allograft h-ADSs and were euthanized on day four after surgery. Similarly, in the AGday8 group, the animals received h-ADSs and were euthanized on day eight after surgery. Microbial colony counts, wound size, stereological parameters, and the expression of microRNA-21 and FGF2 were evaluated in this study during the inflammation (day 4) and proliferation (day 8) stages of wound healing. Results: We demonstrated that h-ADSs significantly reduced microbiological counts compared to the control group on days 4 and 8. Moreover, in the AGday8 group compared to the AGday4 group, this decline in microbiological counts was even more pronounced. Moreover, we observed that the stereological characteristics in the AGday4 and AGday8 groups were significantly superior to those in the CG groups. Additionally, the AGday4 and AGday8 groups exhibited smaller ulcer area sizes compared to the CG groups. Furthermore, the AGday4 and AGday8 groups demonstrated higher expression levels of FGF2 and microRNA-21 than the CG groups on days 4 and 8. Notably, on day 8, the AGday8 group’s outcomes surpassed those of the AGday4 group (P < 0.01). Conclusions: Through lowering microbial counts, modifying stereological parameters, microRNA-21, and FGF2 expression, the administration of hADS dramatically speeds up the healing of MARS-infected and ischemic ulcers in DM1 rats.

Autocatalytically hydroxyl-producing composite wound dressing for bacteria-infected wound healing

The creation of wound dressings with low drug resistance and broad-spectrum antibacterial capability is a key topic of scientific interest. To achieve this, a bactericidal wound dressing with the capacity to autocatalytically produce hydroxyl radicals (OH) was developed. The wound dressing was an electrospun PCL/gelatin/glucose composite fiber mesh (PGD) with functional iron-containing metal-organic framework (Fe-MOF) nanozymes. These functional nanozymes (G@Fe) were formed by coupling glucose oxidase (GOx) and Fe-MOF through amide bonds. These nanozymes enabled the conversion of glucose released from the PGD composite mesh into hydroxyl radicals via an autocatalytic cascade reaction to destroy bacteria. The antibacterial efficiency of wound dressings and their stimulation of tissue regeneration were assessed using a MRSA-infected skin wound infection model on the back of SD mice. The G@Fe/PGD wound dressing exhibited improved wound healing capacity and had comparable biosafety to commercial silver-containing dressings, suggesting a potential replacement in the future.

Antibacterial, antibiofilm, and anti-quorum sensing activities of pyocyanin against methicillin-resistant Staphylococcus aureus: in vitro and in vivo study

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) infections are considered a major public health problem, as the treatment options are restricted. Biofilm formation and the quorum sensing (QS) system play a pivotal role in S. aureus pathogenicity. Hence, this study was performed to explore the antibacterial effect of pyocyanin (PCN) on MRSA as well as its effect on MRSA biofilm and QS.ResultsData revealed that PCN exhibited strong antibacterial activity against all test MRSA isolates (n = 30) with a MIC value equal to 8 µg/ml. About 88% of MRSA biofilms were eradicated by PCN treatment using the crystal violet assay. The disruption of MRSA biofilm was confirmed using confocal laser scanning microscopy, which showed a reduction in bacterial viability (approximately equal to 82%) and biofilm thickness (approximately equal to 60%). Additionally, the disruption of the formation of microcolonies and the disturbance of the connection between bacterial cells in the MRSA biofilm after PCN treatment were examined by scanning electron microscopy. The 1/2 and 1/4 MICs of PCN exerted promising anti-QS activity without affecting bacterial viability; Agr QS-dependent virulence factors (hemolysin, protease, and motility), and the expression of agrA gene, decreased after PCN treatment. The in silico analysis confirmed the binding of PCN to the AgrA protein active site, which blocked its action. The in vivo study using the rat wound infection model confirmed the ability of PCN to modulate the biofilm and QS of MRSA isolates.ConclusionThe extracted PCN seems to be a good candidate for treating MRSA infection through biofilm eradication and Agr QS inhibition.

Antibiotic‐Derived Carbon‐Nanodot‐Decorated Hydrogel for Reactive Oxygen Species‐Enhanced Anti‐Infection Through Biofilm Damage

AbstractIrreversible bacterial resistance and impenetrable biofilms have rendered conventional antibiotic therapy ineffective. Nevertheless, increasing evidence has confirmed that antibiotic carbon nanodots (CDs) exhibit potent antibacterial activity. However, the complex chemical composition of antibiotic CDs, and, hence, their antibacterial mechanism, is difficult to understand. The design of new antibiotic CDs against antibacterial resistance is an urgent requirement.In this study, kanamycin‐sulfate‐derived carbon nanodots (KCDs) are found to exhibit significant antibacterial potential with the assistance of light irradiation. Systematic analysis indicates that KCDs not only retain the active structure of kanamycin but also produce five new components modified on its surface, which are shown to inhibit the activity of Staphylococcus aureus beta‐ketoacyl‐acp synthase III (FabH) through molecular docking. Furthermore, the multifunctional hydrogels (CG‐KCDs) self‐assemble into injectable, self‐healing, and antibiofilm structures through noncovalent forces between the KCDs and cationic guar gum (CG). The results indicate that under laser, CG‐KCDs irradiation exhibits enhanced antibacterial activity in vitro by damaging bacterial biofilms in a reactive oxygen species (ROS)‐dependent manner, as determined by transcriptomics. Further, the therapeutic effects of CG‐KCDs hydrogel dressings on wound healing and tissue remodeling under laser are confirmed using an in vivo wound infection model. These results validate the potential of KCDs as efficient antibacterial agents to replace antibiotics as an anti‐infective strategy.

Dynamic helical cationic polyacetylenes for fast and highly efficient killing of bacteria.

The antimicrobial activity of native antimicrobial peptides (AMPs) is often attributed to their helical structure, but the effectiveness of synthetic mimics with dynamic helical conformations, such as antimicrobial cationic polymers (ACPs), has not been well studied. Herein we demonstrate the antimicrobial activity of pyrrolidinium-pendant polyacetylenes (PAs) with dynamic helical conformations. The PAs exhibit fast and efficient antimicrobial activity against a wide range of pathogens, with low toxicity to mammalian cells and minimal risk of antibiotic resistance. In addition, the full-thickness wound infection model in mice has demonstrated the favorable biocompatibility and effective in vivo antibacterial capabilities of these PAs. Our data suggest that the dynamic helical structure of these PAs allows them to adapt and form pores in the bacterial membrane upon interaction, leading to their potent antimicrobial activity. This work investigated the antibacterial mechanism of dynamic helical ACPs, which provides valuable guidance for the rational design of high-performance antimicrobial agents. STATEMENT OF SIGNIFICANCE: Our study represents a significant contribution to the literature on antimicrobial cationic polymers (ACPs) as alternatives to antibiotics. Through a systematic investigation of the role of dynamic helical conformation in polyacetylenes (PAs) and the use of PAs with adaptive structure for the first time, we have provided valuable insights into the bacterial membrane action and killing mechanisms of these polymers. The results of our study, including fast killing rates and minimum inhibitory concentrations as low as 4-16µg/mL against a broad range of pathogens and strong in vivo antibacterial activity, demonstrate the potential of these ACPs as high-performance antimicrobials. Our findings may guide the design of future ACPs with enhanced antimicrobial activity.

Janus Intelligent Antibacterial Hydrogel Dressings for Chronic Wound Healing in Diabetes

Long-term recurrent infections are one of the significant reasons why chronic diabetic wounds are difficult to heal, and the treatment of chronic wounds remains a major clinical challenge. In this work, we developed a kind of Janus hydrogel dressing capable of adjusting the complex microenvironment of wounds for promoting the healing of diabetic chronic wounds. The Janus hydrogel dressings are made of zwitterionic polymers and gentamicin sulfate-modified hyaluronic acid (HA-GS). One side of the hydrogel dressings was brushed with chitosan to act as a bridge between wound dressings and wound tissues. Thus, the wound dressings showed Janus properties with an antifouling surface on one side and an adhesive surface on the other, where the antifouling surface of zwitterionic hydrogels can avoid the adhesion of external bacteria, while the adhesive surface helps the dressings to be fixed on the wound. Moreover, the antibiotic GS was connected to HA through Schiff’s base, and thus it can be intelligently released in response to the acidic environment of infected wounds to kill the internal bacteria. The Janus hydrogel dressings were carefully characterized and investigated. In vivo results of a diabetic rat infected wound model showed that the Janus hydrogel dressings could effectively inhibit inflammation, accelerate the formation of granulation tissues and collagen deposition, and promote wound healing. Therefore, this multifunctional hydrogel dressing is a promising candidate for chronic wound healing in clinical practice.

Specific Chemiluminescence Imaging and Enhanced Photodynamic Therapy of Bacterial Infections by Hemin-Modified Carbon Dots.

Antibacterial photodynamic therapy (aPDT) is a promising antibiotics-alternative strategy for bacterial infectious diseases, which features broad-spectrum antibacterial activity with a low risk of inducing bacterial resistance. However, clinical applications of aPDT are still hindered by the hydrophobicity-caused inadequate photodynamic activity of conventional photosensitizers and the hypoxic microenvironment of bacterial infections. To address these problems, herein, a promising strategy is developed to achieve specific chemiluminescence (CL) imaging and enhanced PDT of bacterial infections using hemin-modified carbon dots (H-CDs). The H-CDs can be facilely prepared and exhibit favorable water solubility, augmented photodynamic activity, and unique peroxidase-mimicking capacity. Compared with the free CDs, the photodynamic efficacy of H-CDs is significantly augmented due to the increased electron-hole separation efficiency. Moreover, the peroxidase catalytic performance of H-CDs enables not only infection identification via bacterial infection microenvironment-responsive CL imaging but also oxygen self-supplied aPDT with hypoxia-relief-enhanced bacteria inactivation effects. Finally, the enhanced aPDT efficiencies of H-CDs are validated in both in vivo abscess and infected wound models. This work may provide an effective antibacterial platform for the selective imaging-guided treatment of bacterial infections.

Design of Phage-Cocktail-Containing Hydrogel for the Treatment of Pseudomonas aeruginosa-Infected Wounds.

Recently, the treatment of infected wounds has become a global problem due to increased antibiotic resistance in bacteria. The Gram-negative opportunistic pathogen Pseudomonas aeruginosa is often present in chronic skin infections, and it has become a threat to public health as it is increasingly multidrug resistant. Due to this, new measures to enable treatment of infections are necessary. Treatment of bacterial infections with bacteriophages, known as phage therapy, has been in use for a century, and has potential with its antimicrobial effect. The main purpose of this study was to create a phage-containing wound dressing with the ability to prevent bacterial infection and rapid wound healing without side effects. Several phages against P. aeruginosa were isolated from wastewater, and two polyvalent phages were used to prepare a phage cocktail. The phage cocktail was loaded in a hydrogel composed of polymers of sodium alginate (SA) and carboxymethyl cellulose (CMC). To compare the antimicrobial effects, hydrogels containing phages, ciprofloxacin, or phages plus ciprofloxacin were produced, and hydrogels without either. The antimicrobial effect of these hydrogels was investigated in vitro and in vivo using an experimental mouse wound infection model. The wound-healing process in different mouse groups showed that phage-containing hydrogels and antibiotic-containing hydrogels have almost the same antimicrobial effect. However, in terms of wound healing and pathological process, the phage-containing hydrogels performed better than the antibiotic alone. The best performance was achieved with the phage-antibiotic hydrogel, indicating a synergistic effect between the phage cocktail and the antibiotic. In conclusion, phage-containing hydrogels eliminate efficiently P. aeruginosa in wounds and may be a proper option for treating infectious wounds.

Characteristic Metabolic Changes in Skeletal Muscle Due to Vibrio vulnificus Infection in a Wound Infection Model.

Vibrio vulnificus is a bacterium that inhabits warm seawater or brackish water environments and causes foodborne diseases and wound infections. In severe cases, V. vulnificus invades the skeletal muscle tissue, where bacterial proliferation leads to septicemia and necrotizing fasciitis with high mortality. Despite this characteristic, information on metabolic changes in tissue infected with V. vulnificus is not available. Here, we elucidated the metabolic changes in V. vulnificus-infected mouse skeletal muscle using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Metabolome analysis revealed changes in muscle catabolites and energy metabolites during V. vulnificus infection. In particular, succinic acid accumulated but fumaric acid decreased in the infected muscle. However, the virulence factor deletion mutant revealed that changes in metabolites and bacterial proliferation were abolished in skeletal muscle infected with a multifunctional-autoprocessing repeats-in-toxin (MARTX) mutant. On the other hand, mice that were immunosuppressed via cyclophosphamide (CPA) treatment exhibited a similar level of bacterial counts and metabolites between the wild type and MARTX mutant. Therefore, our data indicate that V. vulnificus induces metabolic changes in mouse skeletal muscle and proliferates by using the MARTX toxin to evade the host immune system. This study indicates a new correlation between V. vulnificus infections and metabolic changes that lead to severe reactions or damage to host skeletal muscle. IMPORTANCE V. vulnificus causes necrotizing skin and soft tissue infections (NSSTIs) in severe cases, with high mortality and sign of rapid deterioration. Despite the severity of the infection, the dysfunction of the host metabolism in skeletal muscle triggered by V. vulnificus is poorly understood. In this study, by using a mouse wound infection model, we revealed characteristic changes in muscle catabolism and energy metabolism in skeletal muscle associated with bacterial proliferation in the infected tissues. Understanding such metabolic changes in V. vulnificus-infected tissue may provide crucial information to identify the mechanism via which V. vulnificus induces severe infections. Moreover, our metabolite data may be useful for the recognition, identification, or detection of V. vulnificus infections in clinical studies.

Ferric chloride induces ferroptosis in Pseudomonas aeruginosa and heals wound infection in a mouse model

As one of the most common pathogens leading to fatal human infection, Pseudomonas aeruginosa has been evolving complex drug resistance, posing significant challenges to the current antibiotic-dependent healthcare system. New therapeutic approaches are urgently required to treat infections caused by P. aeruginosa. Inspired by ferroptosis, we investigated the antibacterial effects of iron compounds on P. aeruginosa via direct exposure, and developed thermal-responsive hydrogels to carry FeCl3 as a wound dressing to treat P. aeruginosa-induced wound infection in mice model. The results showed that 200 μM FeCl3 killed more than 99.9% P. aeruginosa cells. The FeCl3-mediated cell death in P. aeruginosa was associated with ferroptosis hallmarks of mammal cells, e.g., reactive oxygen species (ROS) burst, lipid peroxidation, and DNA damage. Either catalase or Fe2+ chelator alleviated the FeCl3-mediated cell death, indicating that H2O2 and labile Fe2+ facilitated the Fenton reaction leading to the cell death. Further proteomics analysis showed that proteins related to glutathione (GSH) synthesis and glutathione peroxidase (GPX) family were significantly down-regulated after FeCl3 treatment, equivalent to GPX4 inactivation in ferroptosis-occurring mammal cells. We further evaluated the therapeutic effect of FeCl3 on P. aeruginosa in a mouse wound infection model using polyvinyl alcohol-boric acid (PB) hydrogels as the carrier of FeCl3. Strikingly, FeCl3-PB hydrogels completely cleared pus on wounds and promoted the healing of wounds. These results indicated that FeCl3 facilitates microbial ferroptosis in the gram-negative pathogen P. aeruginosa and has high therapeutic potential in P. aeruginosa wound infection.

Essential Oil Nanoemulsion Hydrogel with Anti-Biofilm Activity for the Treatment of Infected Wounds.

The formation of a bacterial biofilm on an infected wound can impede drug penetration and greatly thwart the healing process. Thus, it is essential to develop a wound dressing that can inhibit the growth of and remove biofilms, facilitating the healing of infected wounds. In this study, optimized eucalyptus essential oil nanoemulsions (EEO NEs) were prepared from eucalyptus essential oil, Tween 80, anhydrous ethanol, and water. Afterward, they were combined with a hydrogel matrix physically cross-linked with Carbomer 940 (CBM) and carboxymethyl chitosan (CMC) to prepare eucalyptus essential oil nanoemulsion hydrogels (CBM/CMC/EEO NE). The physical-chemical properties, in vitro bacterial inhibition, and biocompatibility of EEO NE and CBM/CMC/EEO NE were extensively investigated and the infected wound models were proposed to validate the in vivo therapeutic efficacy of CBM/CMC/EEO NE. The results showed that the average particle size of EEO NE was 15.34 ± 3.77 nm with PDI ˂ 0.2, the minimum inhibitory concentration (MIC) of EEO NE was 15 mg/mL, and the minimum bactericidal concentration (MBC) against S. aureus was 25 mg/mL. The inhibition and clearance of EEO NE against S. aureus biofilm at 2×MIC concentrations were 77.530 ± 7.292% and 60.700 ± 3.341%, respectively, demonstrating high anti-biofilm activity in vitro. CBM/CMC/EEO NE exhibited good rheology, water retention, porosity, water vapor permeability, and biocompatibility, meeting the requirements for trauma dressings. In vivo experiments revealed that CBM/CMC/EEO NE effectively promoted wound healing, reduced the bacterial load of wounds, and accelerated the recovery of epidermal and dermal tissue cells. Moreover, CBM/CMC/EEO NE significantly down-regulated the expression of two inflammatory factors, IL-6 and TNF-α, and up-regulated three growth-promoting factors, TGF-β1, VEGF, and EGF. Thus, the CBM/CMC/EEO NE hydrogel effectively treated wounds infected with S. aureus, enhancing the healing process. It is expected to be a new clinical alternative for healing infected wounds in the future.

Ag/Ag2O with NIR-Triggered Antibacterial Activities: Photocatalytic Sterilization Enhanced by Low-Temperature Photothermal Effect.

A synergistic antibacterial system employing photocatalytic performance and low-temperature photothermal effect (LT-PTT) with the potential for infectious skin wound healing promotion was developed. Ag/Ag2O was synthesized with a two-step method, and its physicochemical properties were characterized. After its photocatalytic performance and photothermal effect were evaluated under 0.5 W/cm2 808 nm NIR laser irradiation, its antibacterial activities in both planktonic and biofilm forms were then studied in vitro targeting Staphylococcus Aureus (S. aureus), and the biocompatibility was tested with L-929 cell lines afterward. Finally, the animal model of dorsal skin wound infection was established on Sprague-Dawley rats and was used to assess infectious wound healing promotion of Ag/Ag2O in vivo. Ag/Ag2O showed boosted photocatalytic performance and local temperature accumulation compared with Ag2O when exposed to 0.5 W/cm2 808 nm NIR irradiation, which therefore endowed Ag/Ag2O with the ability to kill pathogens rapidly and cleavage bacterial biofilm in vitro. Furthermore, after treatment with Ag/Ag2O and 0.5 W/cm2 808 nm NIR irradiation, infectious wounds of rats realized skin tissue regeneration from a histochemical level. By exhibiting excellent NIR-triggered photocatalytic sterilization ability enhanced by low-temperature photothermal effect, Ag/Ag2O was promising to be a novel, photo-responsive antibacterial agent.

Multi-crosslinked hydrogels with strong wet adhesion, self-healing, antibacterial property, reactive oxygen species scavenging activity, and on-demand removability for seawater-immersed wound healing.

In general, seawater-immersed wounds are associated with tissue necrosis, infection, prolonged healing period, and high mortality because of high salinity, hyperosmosis, and the presence of various pathogenic bacteria in seawater. However, current wound dressings can hardly achieve strong and stable wet adhesion and antibacterial properties, thus limiting their application to seawater-immersed wounds. Here a multifunctional hydrogel (OD/EPL@Fe) comprising catechol-modified oxidized hyaluronic acid (OD), ε-poly-L-lysine (EPL), and Fe3+ was prepared primarily through Schiff-base reaction, metal chelation, cation-π, and electrostatic interaction. The hydrogel with high wet adhesion (about 78 kPa) was achieved by combining the mussel-inspired strategy, dehydration effect, and cohesion enhancement, which is higher than that of commercial fibrin glues and cyanoacrylate glues. Meanwhile, the hydrogel can eliminate Marine bacteria (V. vulnificus and P. aeruginosa) and inhibit their biofilm formation. In addition, the hydrogel demonstrated injectability, self-healing, reactive oxygen species scavenging activity, photothermal effect, seawater isolation, on-demand removal, and hemostatic properties. In vivo results showed that the hydrogel had good adhesion to dynamic wounds in a rat neck full-thickness skin wound model. In particular, the hydrogel exhibited antibacterial, anti-inflammatory, and antioxidant properties in a rat seawater-immersed infected wound model and accelerated the reconstruction of skin structure and functions. The results demonstrated that the OD/EPL@Fe would be a potential wound dressing for seawater-immersed wound healing. STATEMENT OF SIGNIFICANCE: A multifunctional OD/EPL@Fe hydrogel has been prepared for the treatment of seawater-immersed wounds. The hydrogel with high wet adhesion was achieved by combining the mussel-inspired strategy, dehydration effect, and cohesion enhancement. The results revealed that the wet adhesion value of hydrogel was about eight times greater than commercial fibrin glues and 1.5 times greater than commercial cyanoacrylate glues. The hydrogel can be easily removed after being sprayed with deferoxamine mesylate. Notably, the inherent antimicrobial material of the hydrogel combined with the photothermal effect can eliminate marine bacteria and inhibit their biofilm formation. Moreover, the hydrogel can accelerate the healing of seawater-immersed infected wound on mice.

Mitoxantrone targets both host and bacteria to overcome vancomycin resistance in Enterococcus faecalis.

Antibiotic resistance critically limits treatment options for infection caused by opportunistic pathogens such as enterococci. Here, we investigate the antibiotic and immunological activity of the anticancer agent mitoxantrone (MTX) in vitro and in vivo against vancomycin-resistant Enterococcus faecalis (VRE). We show that, in vitro, MTX is a potent antibiotic against Gram-positive bacteria through induction of reactive oxygen species and DNA damage. MTX also synergizes with vancomycin against VRE, rendering the resistant strains more permeable to MTX. In a murine wound infection model, single-dose MTX treatment effectively reduces VRE numbers, with further reduction when combined with vancomycin. Multiple MTX treatments accelerate wound closure. MTX also promotes macrophage recruitment and proinflammatory cytokine induction at the wound site and augments intracellular bacterial killing in macrophages by up-regulating the expression of lysosomal enzymes. These results show that MTX represents a promising bacterium- and host-targeted therapeutic for overcoming vancomycin resistance.

Click-crosslinked in-situ hydrogel improves the therapeutic effect in wound infections through antibacterial, antioxidant and anti-inflammatory activities

Bacterial infection, free radical accumulation and excessive inflammation are major factors leading to delayed wound healing. The rapid and effective elimination of wound bacteria and excess free radicals, and modulation of the wound immune microenvironment to accelerate infected wound healing is one of the pressing clinical issues. Common wound dressing or drugs are single-functional and risk of developing drug resistance. Therefore, multifunctional biomaterials with accelerated wound healing are urgently desired. Herein, we reported a click-crosslinked hydrogel with antibacterial, antioxidant and anti-inflammatory properties for infected wound repair. The hydrogel gelated from maleimide-based oxidized sodium alginate and sulfhydryl carboxymethyl chitosan based on “click” chemistry and Schiff base reaction possess short gelation time, good biocompatibility, broad-spectrum antibacterial activity, appropriate antioxidant and anti-inflammatory ability. Hydrogels effectively activate macrophage polarization toward the M2 phenotype and significantly promote the migration of repair-related cells (fibroblasts, epithelial cells and endothelial cells) and angiogenesis in vitro through paracrine mechanism. The in vivo results from a full-thickness infected wound model demonstrated that hydrogels can promote wound repair and regeneration by promoting angiogenesis and re-epithelialization through antibacterial, antioxidant and M2-type macrophage polarization. The bioactive hydrogels designed with antibacterial, antioxidant and M2 polarization promoting properties provide an efficient strategy for infected wound repair.

A hydrogel-based first-aid tissue adhesive with effective hemostasis and anti-bacteria for trauma emergency management

BackgroundClinical tissue adhesives remain some critical drawbacks for managing emergency injuries, such as inadequate adhesive strength and insufficient anti-infection ability. Herein, a novel, self-healing, and antibacterial carboxymethyl chitosan/polyaldehyde dextran (CMCS/PD) hydrogel is designed as the first-aid tissue adhesive for effective trauma emergency management.MethodsWe examined the gel-forming time, porosity, self-healing, antibacterial properties, cytotoxicity, adhesive strength, and hemocompatibility. Liver hemorrhage, tail severance, and skin wound infection models of rats are constructed in vivo, respectively.ResultsResults demonstrate that the CMCS/PD hydrogel has the rapid gel-forming (~ 5 s), good self-healing, and effective antibacterial abilities, and could adhere to tissue firmly (adhesive strength of ~ 10 kPa and burst pressure of 327.5 mmHg) with excellent hemocompatibility and cytocompatibility. This suggests the great prospect of CMCS/PD hydrogel in acting as a first-aid tissue adhesive for trauma emergency management. The CMCS/PD hydrogel is observed to not only achieve rapid hemostasis for curing liver hemorrhage and tail severance in comparison to commercial hemostatic gel (Surgiflo ®) but also exhibit superior anti-infection for treating acute skin trauma compared with clinical disinfectant gel (Prontosan ®).ConclusionsOverall, the CMCS/PD hydrogel offers a promising candidate for first-aid tissue adhesives to manage the trauma emergency. Because of the rapid gel-forming time, it could also be applied as a liquid first-aid bandage for mini-invasive surgical treatment.Graphical

The pH‐Sensitive Optical Fiber Integrated CMCS‐PA@Fe Hydrogels for Photothermal Therapy and Real‐Time Monitoring of Infected Wounds

AbstractBacterial infections are one of the biggest threats to wound healing. Despite significant efforts in wound condition monitoring and treatment, significant challenges remain in real‐time wound monitoring and timely treatment. Herein, a kind of hydrogel with dual functions, which can not only quickly diagnose wound bacterial infection but also provide timely and effective treatment is developed. First, Carborxymethy chitosan (CMCS)‐Protocatechualdehyde (PA)@Fe hydrogels with double dynamic bonds are prepared by chelating PA@Fe with CMCS. Second, the pH‐sensitive Polydimethylsiloxane (PDMS) optical fibers are integrated into the CMCS‐PA@Fe hydrogels to obtain the pH‐sensitive optical fiber/CMCS‐PA@Fe hydrogels that exhibit good real‐time monitoring of the wound healing process. The tissue adhesion and self‐healing properties of the pH‐sensitive optical fiber/CMCS‐PA@Fe hydrogels can adapt to the movement and stretching of the skin. Meanwhile, with the assistance of the photothermal effect, the hydrogels have a high antibacterial effect (>99.9%). In addition, the pH‐sensitive optical fiber/CMCS‐PA@Fe hydrogels also show an excellent therapeutic effect in the wound infection model. Moreover, reliable and timely wound pH information can be sent to intelligent devices through microcomputers to monitor the healing status. Overall, the pH‐sensitive optical fiber/CMCS‐PA@Fe hydrogels provide an entirely new platform for developing smart, real‐time diagnostics and timely wound treatment.

Effective decolonization strategy for mupirocin-resistant Staphylococcus aureus by TPGS-modified mupirocin-silver complex.

The widespread utilization of mupirocin to treat methicillin-resistant Staphylococcus aureus (MRSA)-caused infectious diseases has led to the emergence of mupirocin-resistant Staphylococcus aureus (MuRSA), posing a serious global medical threat. In order to counteract MuRSA, we develop a d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) modified mupirocin and silver complex (TPGS/Mup-Ag) to combat MuRSA. The surfactivity of TPGS endows Mup-Ag with a homogeneous and small particle size (∼16​nm), which significantly enhances bacterial internalization. Silver ions are released from the mupirocin-Ag complex (Mup-Ag) to exert a synergistic antibacterial activity with mupirocin. Results manifest that our strategy reduces the concentration of mupirocin that induces 50% bacterial death from about 1000​μmol/mL to about 16​μmol/mL. In vitro bacterial infection model suggests that TPGS/Mup-Ag can not only eliminate both intracellular and inhibit bacterial adhesion, but also living cells are not affected. Results of in vivo experiments demonstrate that TPGS/Mup-Ag can effectively inhibit the progression of skin infection and accelerate wound healing, as well as alleviate systemic inflammation in both the subcutaneous infection model and the wound infection model. Furthermore, this study may contribute to the development of therapeutic agents for antibiotic-resistant bacteria and offer ideas for silver-based bactericides.

Small Molecule IITR00693 (2-Aminoperimidine) Synergizes Polymyxin B Activity against Staphylococcus aureus and Pseudomonas aeruginosa.

The rise of antibiotic resistance among skin-infecting pathogens poses an urgent threat to public health and has fueled the search for new therapies. Enhancing the potency of currently used antibiotics is an alternative for the treatment of infections caused by drug-resistant pathogens. In this study, we aimed to identify a small molecule that can potentiate currently used antibiotics. IITR00693 (2-aminoperimidine), a novel antibacterial small molecule, potentiates the antibacterial activity of polymyxin B against Staphylococcus aureus and Pseudomonas aeruginosa. Herein, we investigated in detail the mode of action of this interaction and the molecule's capability to combat soft-tissue infections caused by S. aureus and P. aeruginosa. A microdilution checkerboard assay was performed to determine the synergistic interaction between polymyxin B and IITR00693 in clinical isolates of S. aureus and P. aeruginosa. Time-kill kinetics, post-antibiotic effect, and resistance generation studies were performed to assess the pharmacodynamics of the combination. Assays based on different fluorescent probes were performed to decipher the mechanism of action of this combination. The in vivo efficacy of the IITR00693-polymyxin B combination was determined in a murine acute wound infection model. IITR00693 exhibited broad-spectrum antibacterial activity. IITR00693 potentiated polymyxin B and colistin against polymyxin-resistant S. aureus. IITR00693 prevented the generation of resistant mutants against multiple antibiotics. The IITR00693-polymyxin B combination decreased the S. aureus count by >3log10 CFU in a murine acute wound infection model. IITR00693 is a potential and promising candidate for the treatment of soft-tissue infections along with polymyxins.

Development of In Vitro and Ex Vivo Biofilm Models for the Assessment of Antibacterial Fibrous Electrospun Wound Dressings

Increasing evidence suggests that the chronicity of wounds is associated with the presence of bacterial biofilms. Therefore, novel wound care products are being developed, which can inhibit biofilm formation and/or treat already formed biofilms. A lack of standardized assays for the analysis of such novel antibacterial drug delivery systems enhances the need for appropriate tools and models for their characterization. Herein, we demonstrate that optimized and biorelevant in vitro and ex vivo wound infection and biofilm models offer a convenient approach for the testing of novel antibacterial wound dressings for their antibacterial and antibiofilm properties, allowing one to obtain qualitative and quantitative results. The in vitro model was developed using an electrospun (ES) thermally crosslinked gelatin-glucose (GEL-Glu) matrix and an ex vivo wound infection model using pig ear skin. Wound pathogens were used for colonization and biofilm development on the GEL-Glu matrix or pig skin with superficial burn wounds. The in vitro model allowed us to obtain more reproducible results compared with the ex vivo model, whereas the ex vivo model had the advantage that several pathogens preferred to form a biofilm on pig skin compared with the GEL-Glu matrix. The in vitro model functioned poorly for Staphylococcus epidermidis biofilm formation, but it worked well for Escherichia coli and Staphylococcus aureus, which were able to use the GEL-Glu matrix as a nutrient source and not only as a surface for biofilm growth. On the other hand, all tested pathogens were equally able to produce a biofilm on the surface of pig skin. The developed biofilm models enabled us to compare different ES dressings [pristine and chloramphenicol-loaded polycaprolactone (PCL) and PCL-poly(ethylene oxide) (PEO) (PCL/PEO) dressings] and understand their biofilm inhibition and treatment properties on various pathogens. Furthermore, we show that biofilms were formed on the wound surface as well as on a wound dressing, indicating that the demonstrated methods mimic well the in vivo situation. Colony forming unit (CFU) counting and live biofilm matrix as well as bacterial DNA staining together with microscopic imaging were performed for biofilm quantification and visualization, respectively. The results showed that both wound biofilm models (in vitro and ex vivo) enabled the evaluation of the desired antibiofilm properties, thus facilitating the design and development of more effective wound care products and screening of various formulations and active substances.