Bimetallic-Gallic Acid Cross-Linked Hydrogels with Cascading Nanozyme Activity Promote Healing of MRSA-Infected Wounds by Modulating the Oxidative Stress Microenvironment.

The mesenchymal stromal cell secretome promotes tissue regeneration and increases macrophage infiltration in acute and methicillin-resistant Staphylococcus aureus-infected skin wounds in vivo

Background and Aim: The high prevalence of diabetes mellitus in Indonesia indirectly reflects the high risk of developing chronic wounds that are susceptible to infection. Methicillin-resistant Staphylococcus aureus (MRSA) is an infectious pathogen that is resistant to various antibiotics. Therefore, antibiotic therapy is ineffective enough to treat chronic hyperglycemic wounds caused by MRSA infection. Curcuminoids have anti-inflammatory and antibacterial effects by inhibiting the enzymatic pathways involved in the pathogenesis of inflammation. Collagen is a tissue regeneration inducer. The combination of these two ingredients is expected to be an alternative therapy for MRSA-infected hyperglycemic chronic wounds without the risk of antibiotic resistance. The aim of this study was to investigate the efficacy of hydrolacin-gel in wound healing and inhibiting the growth of MRSA bacteria, as well as to determine the optimal concentration of curcuminoids combined with collagen marine peptides (CMPs). Materials and Methods: Hydrolacin-gels were prepared by homogenizing curcuminoid nanoemulsions and CMPs. The evaluation of preparation includes stability tests and antibacterial activity tests. Wound diabetic mice were treated with various combinations of curcuminoid and CMPs. Wound healing was observed based on malondialdehyde levels as a marker of oxidative stress and histopathological changes in the skin wound. Results: Hydrolacin-gel was formulated by combining curcuminoid nanoemulsion (more water soluble) and CMPs, with the ratio of formula 1 (1:2, curcuminoid 43.3 mg and CMPs 5.58 mg), formula 2 (1:1, curcuminoid 86.8 mg and CMPs 3.72), and formula 3 (2:1, curcuminoid 130.2 mg and CMPs 1.87 mg) calculated based on the effective dose of curcuminoid 200 mg/kg body weight (BW) and CAMPs 0.9 g/kg BW. Hydrolacin-gel had a potential antibacterial activity against MRSA. Hydrolacin-gel induced wound tissue repair and reduced oxidative stress caused by inflammation in diabetic-infected MRSA. Hydrolacin-gel could be used for healing MRSA-infected diabetic wounds, especially formula 3 with the ratio of curcuminoid: CMPs = 2:1. Conclusion: Hydrolacin-gel combining curcuminoid nanoemulsion and CMPs effectively inhibited the inflammatory process and increased re-epithelialization in MRSA-infected diabetic wound healing. Hydrolacin-gel with curcuminoid (130.2 mg) and CMPs (1.87 mg) at a concentration ratio of 2:1 appeared to be the best formula against MRSA infection in diabetic wounds. Keywords: collagen marine peptides, curcuminoids, diabetic, methicillin-resistant Staphylococcus aureus, wound.

The repair of chronic and infected wounds continues to present significant clinical challenges, including prolonged inflammation, impaired angiogenesis, and imbalances in the biomechanical microenvironment. This study developed an innovative thermoresponsive gel integrating Salvia miltiorrhiza-derived carbon dots (SM-CDs), designed to accelerate wound healing through a "biochemical-mechanical" synergistic regulation strategy. First, SM-CDs were synthesized via hydrothermal method. These CDs retained the triple bioactivity of S. miltiorrhiza, encompassing antimicrobial, antioxidant, and pro-angiogenic properties, thereby enhancing their interaction with biofilms and bioavailability. Second, a multistep cross-linking strategy was employed to construct a ternary gel network (denoted PCS gel) composed of N-isopropylacrylamide (NIPAM), carboxymethyl chitosan (CMCS), and sodium alginate (SA). This system demonstrated efficient drug release (67.12% cumulative release over 72 h) and mechanical contraction (83.99% volume contraction ratio) at 37 °C. These effects are attributed to the phase transition behavior of NIPAM and the electrostatic/ionic cross-linking mechanisms of CMCS/SA. In vitro and in vivo studies revealed that the SM-CDs@PCS gel promotes wound healing through a dual mechanism: (1) Biochemical modulation: suppressing oxidative stress (91% ROS scavenging rate) and inflammatory responses (TNF-α downregulated to 16.25 ± 2.69%; IL-6 downregulated to 10.49 ± 2.04%), polarizing macrophages toward the pro-repair M2 phenotype (M2/M1 ratio = 1.69 ± 0.11), and promoting angiogenesis; (2) Mechanical modulation: enhancing collagen deposition through the gel's biomechanical contraction effect, thereby accelerating wound closure. This research provides insights into the application of herbal medicine-derived CDs materials and intelligent gels for the management of hard-to-heal wounds.

Pseudomonas aeruginosa (PA) is an opportunistic pathogen frequently isolated from cutaneous chronic wounds. How PA, in the presence of oxidative stress (OS), colonizes chronic wounds and forms a biofilm is still unknown. The purpose of this study is to investigate the changes in gene expression seen when PA is challenged with the high levels of OS present in chronic wounds. We used a biofilm-forming PA strain isolated from the chronic wounds of our murine model (RPA) and performed a qPCR to obtain gene expression patterns as RPA developed a biofilm in vitro in the presence of high levels of OS, and then compared the findings in vivo, in our mouse model of chronic wounds. We found that the planktonic bacteria under OS conditions overexpressed quorum sensing genes that are important for the bacteria to communicate with each other, antioxidant stress genes important to reduce OS in the microenvironment for survival, biofilm formation genes and virulence genes. Additionally, we performed RNAseq in vivo and identified the activation of novel genes/pathways of the Type VI Secretion System (T6SS) involved in RPA pathogenicity. In conclusion, RPA appears to survive the high OS microenvironment in chronic wounds and colonizes these wounds by turning on virulence, biofilm-forming and survival genes. These findings reveal pathways that may be promising targets for new therapies aimed at disrupting PA-containing biofilms immediately after debridement to facilitate the treatment of chronic human wounds.

Skin wound healing is a complex biological process that requires the regulation of different cell types, including immune cells, keratinocytes, fibroblasts, and endothelial cells. It consists of 5 stages: hemostasis, inflammation, granulation tissue formation, re-epithelialization, and wound remodeling. While inflammation is essential for successful wound healing, prolonged or excess inflammation can result in nonhealing chronic wounds. Lactoferrin, an iron-binding glycoprotein secreted from glandular epithelial cells into body fluids, promotes skin wound healing by enhancing the initial inflammatory phase. Lactoferrin also exhibits anti-inflammatory activity that neutralizes overabundant immune response. Accumulating evidence suggests that lactoferrin directly promotes both the formation of granulation tissue and re-epithelialization. Lactoferrin stimulates the proliferation and migration of fibroblasts and keratinocytes and enhances the synthesis of extracellular matrix components, such as collagen and hyaluronan. In an in vitro model of wound contraction, lactoferrin promoted fibroblast-mediated collagen gel contraction. These observations indicate that lactoferrin supports multiple biological processes involved in wound healing.

Background: Polysaccharide-based dynamic hydrogels are promising for wound management due to their biocompatibility, injectability, and tunable biofunctionality. The integration of therapeutic gasotransmitter donors offers a strategy to modulate the wound microenvironment. Objectives: This study aimed to develop an injectable, self-healing carbohydrate hydrogel capable of sustained hydrogen sulfide (H2S) release for burn wound therapy, and to evaluate its physicochemical properties, in vivo efficacy, and mechanism of action. Methods: A dynamic hydrogel (ACMOD) was fabricated via Schiff-base crosslinking between oxidized dextran (OD) and carboxymethyl chitosan (CMCS), incorporating the H2S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH). Rheological and recovery tests characterized its mechanical and self-healing properties. Efficacy and mechanisms were assessed in a rat full-thickness burn model, analyzing wound closure, histology, oxidative stress, macrophage polarization, angiogenesis, and collagen deposition. Results: ACMOD exhibited shear-thinning, rapid self-healing, and strong tissue adherence. Sustained H2S release from ACMOD significantly accelerated wound closure and improved tissue regeneration compared to controls. Mechanistically, H2S attenuated oxidative stress, promoted a pro-regenerative M2 macrophage phenotype, enhanced angiogenesis via VEGF upregulation, and fostered organized collagen deposition and extracellular matrix remodeling. Conclusions: This work demonstrates a versatile, carbohydrate-based dynamic hydrogel platform that synergizes polymer network dynamics with bioactive H2S delivery to effectively promote burn wound healing. The findings underscore the potential of polysaccharide hydrogels with integrated gasotransmitter release for regenerative therapy and biomaterials applications.

Health-Care-Associated Pneumonia

Introduction: Prevention and management of biofilm in acute and chronic wounds in ICU settings is critical, as biofilm significantly impedes wound healing. Approximately 90% of all wounds are affected by biofilm. It is not feasible to eliminate biofilm using a single wound-cleaning technology. Early intervention and the combined use of multiple technologies for biofilm removal are essential to promote wound healing. Rapid and effective treatment is vital to prevent severe complications such as infections or amputations in intensive care units. Drawing on extensive knowledge of available technologies and their mechanisms of action, we adopted a multimodal approach to treat wounds with biofilm. The primary objective was to prevent and manage biofilm in both acute and chronic wounds. Methods: Five patients with infected acute and traumatic wounds—including chronic osteomyelitis tunnel wound, gunshot injuries, shrapnel wounds, surgical incisions, and fasciotomies—underwent Three-Step Multimodal Biofilm-Focused Protocol consisting of three sequential steps: Step 1: Cleansing and moistening wounds with a solution containing active pure HOCl (pH 2.5) for at least 30 minutes. Step 2: Cleansing and moistening wounds with a polyhexamethylene biguanide (PHMB) and betaine solution, left in place for 30 minutes, followed by cleaning with a debridement pad. Step 3: Application of a synergistic ionic silver (0.01%)–menthol liquid dressing with unique properties (cleansing, disinfecting, removing waste and slough, destroying biofilm). This dressing offers broad-spectrum antibacterial activity and accelerates healing. Wet pads were left in the wounds for the remainder of the day. Results / Discussion: All wounds demonstrated improvement, with the formation of new granulation tissue. Subsequent treatments included negative pressure therapy, secondary surgical closure, or skin grafting. Gunshot and shrapnel wounds healed successfully, limb amputation was avoided, and the chronic osteomyelitis tunnel wound contracted. This Three-Step Multimodal Biofilm-Focused Protocol enhanced wound healing, prevented amputations, and accelerated recovery. The method was later applied to other complex wounds in ICU patients.

Collagen-oxidized hyaluronic acid injectable self-healing hydrogel enabling sequential platelet-rich plasma release for microenvironment modulation in diabetic wound repair.

Since the introduction of vacuum-assisted closure (VAC) in 1997, it has been used successfully in treating difficult wounds, including spinal wounds and wounds in pediatric patients. There are no reports on VAC therapy in pediatric patients on the scalp, especially with exposed dura. This report describes a 10-year-old boy with a chronic wound of the scalp with exposed dura after multiple neurosurgical interventions who was treated successfully with VAC. A 10-year-old mentally disabled boy with Apert syndrome suffered from a chronic wound with community-associated methicillin-resistant Staphylococcus aureus (MRSA) infection after multiple neurosurgeon operations. For wound closure, VAC therapy was initiated on the bony defect with exposed dura. The wound healed successfully, and the MRSA disappeared. The aims of VAC therapy are formation of new granulation tissue, wound cleansing, and bacterial clearance. In this case, the VAC device was excellent for temporary coverage of the defect and for wound cleaning, and it allowed a thick bed of granulation tissue to form over the dura, even with minimal constant negative pressure. The application and management were feasible even in a mentally disabled child. With this experience, we are encouraged to use the VAC device in difficult wounds, even in the head and neck area in children, and to bring this treatment into the outpatient clinic.

Objectives: Excessive reactive oxygen species (ROS) in diabetic wounds are major contributors to chronic wounds and impaired healing, posing significant challenges in regenerative medicine. Developing innovative drug delivery systems is crucial to address these issues by modifying the adverse microenvironment and promoting effective wound healing. Methods: Herein, we designed a novel drug delivery platform using manganese dioxide nanoflower hybridized gold nanoparticle composites (MnO2-Au) synthesized via a hydrothermal reaction, and investigated the potential of MnO2-Au nanoflowers to relieve the high oxidative stress microenvironment and regulate diabetic wound tissue healing. Results: This hybrid material demonstrated superior catalytic activity compared to MnO2 alone, enabling the rapid decomposition of hydrogen peroxide and a substantial reduction in ROS levels within dermal fibroblasts. The MnO2-Au nanoflowers also facilitated enhanced dermal fibroblast migration and Col-I expression, which are critical for tissue regeneration. Additionally, a hydrogel-based wound dressing incorporating MnO2-Au nanoflowers was developed, showing its potential as an intelligent drug delivery system. This dressing significantly reduced oxidative stress, accelerated wound closure, and improved the quality of neonatal epithelial tissue regeneration in a diabetic rat skin defect model. Conclusions: Our findings underscore the potential of MnO2-Au nanoflower-based drug delivery systems as a promising therapeutic approach for chronic wound healing, particularly in regenerative medicine.

Chronic wounds, including diabetic ulcers (DUs), radiation-induced ulcers, and burns, present significant clinical challenges due to their distinct pathological mechanisms, necessitating tailored therapeutic strategies. Diabetic ulcers, characterized by impaired angiogenesis, persistent inflammation, and hyperglycemia, require dual modulation of inflammatory (NF-κB) and pro-repair (PI3K/Akt, Nrf2) pathways. Radiation ulcers involve DNA damage, NLRP3-driven inflammation, and TGF-β/Smad-mediated fibrosis, while burns trigger acute inflammation via DAMPs/PAMPs-TLR/NLR activation. Traditional Chinese medicine (TCM) and its bioactive components, such as Scutellaria baicalensis, curcumin, and Panax notoginseng, exhibit multi-target therapeutic effects by regulating oxidative stress, inflammation, angiogenesis, and extracellular matrix remodeling through key pathways, including Nrf2/ARE, MAPK, NF-κB, PI3K/Akt, HIF-1α/VEGF, Wnt/β-catenin, and TGF-β/Smad. Emerging supramolecular self-assembled biomaterials—nanofibrous scaffolds, hydrogels, and microneedles—address the hydrophobicity and low bioavailability of natural plant-derived macromolecules (NPHMs), enabling spatiotemporally controlled drug delivery. Innovative formulations, such as curcumin-loaded hydrogels and exosome-based systems, enhance antioxidant, anti-inflammatory, and pro-angiogenic activities, accelerating wound closure. Despite progress, challenges remain in optimizing multifunctional co-assembly systems, elucidating NPHM self-assembly mechanisms, and developing smart biomaterials responsive to dynamic wound microenvironments. Future research should focus on clinical translation by improving material stability, refining stimulus-responsive release systems, and integrating interdisciplinary insights from herbal medicine, nanotechnology, and regenerative biology. This review systematically summarizes the mechanistic roles of TCM in wound healing, highlights advancements in bioactive material design, and outlines future directions to bridge traditional knowledge with modern therapeutic innovations, offering a scientific foundation for advancing chronic wound management.

Snail-inspired AFG/GelMA hydrogel accelerates diabetic wound healing via inflammatory cytokines suppression and macrophage polarization

Chronic wounds in diabetic patients are associated with significant morbidity and mortality; however, few therapies are available to improve healing of diabetic wounds. Our group previously reported that low-intensity vibration (LIV) could improve angiogenesis and wound healing in diabetic mice. The purpose of this study was to begin to elucidate the mechanisms underlying LIV-enhanced healing. We first demonstrate that LIV-enhanced wound healing in db/db mice is associated with increased IGF1 protein levels in liver, blood, and wounds. The increase in insulin-like growth factor (IGF) 1 protein in wounds is associated with increased Igf1 mRNA expression both in liver and wounds, but the increase in protein levels preceded the increase in mRNA expression in wounds. Since our previous study demonstrated that liver was a primary source of IGF1 in skin wounds, we used inducible ablation of IGF1 in the liver of high-fat diet (HFD)-fed mice to determine whether liver IGF1 mediated the effects of LIV on wound healing. We demonstrate that knockdown of IGF1 in liver blunts LIV-induced improvements in wound healing in HFD-fed mice, particularly increased angiogenesis and granulation tissue formation, and inhibits the resolution of inflammation. This and our previous studies indicate that LIV may promote skin wound healing at least in part via crosstalk between the liver and wound. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A novel chlorin derivative Shengtaibufen (STBF) mediated photodynamic therapy combined with iodophor for the treatment of chronic superficial leg wounds infected with methicillin-resistant Staphylococcus aureus: A retrospective clinical study