Multifunctional bilayered nanofibrous scaffold of chitosan/poly(caprolactone) enriched with simvastatin and thymoquinone for accelerated diabetic wound healing.

Background. Chronic diabetic foot ulcers and wounds are significant complications associated with diabetes, comprising approximately 85% of purulent-necrotic lesions affecting the lower extremities. The development of these wounds is influenced by pathogenetic factors such as hyperglycemia, neuropathy, and existing infections, which contribute to metabolic disturbances, including tissue hypoxia and the activation of proteolytic enzymes known as matrix metalloproteinases (MMPs). Aim. To explore the therapeutic potential of autologous plasminogen in facilitating the healing process of diabetic wounds through the modulation of MMP activity. Materials and Methods. The study enrolled 45 patients diagnosed with chronic diabetic wounds, who were assigned to two distinct groups. The control group (n=25) received conventional treatment approaches, while the intervention group consisted of 20 patients treated with autologous plasminogen applications. Results. After 18 days of treatment, a substantial reduction of 3.5-fold in MMP-2 and MMP-9 activity was observed within the intervention group, accompanied by complete wound closure in 16 patients. Additionally, four patients underwent autodermoplasty, successfully achieving wound defect closure through effective graft integration. In contrast, the control group exhibited consistently elevated MMP activity levels throughout the entire observation period. Conclusions. The activity of matrix metalloproteinases (MMPs) in chronic diabetic wounds reaches dramatic levels, making spontaneous wound healing impossible. The application of autologous Pg allows modulation of this activity and creates favorable conditions for wound healing by reducing excessive MMP activity, improving blood supply, and resolving inflammatory processes. Keywords: chronic wounds, diabetes mellitus, matrix metalloproteinases, plasminogen, autodermoplasty.

Chapter 11 - Role of cytokines and chemokines in wound healing

Hypoxia and infection are urgent clinical problems in chronic diabetic wounds. Herein, living Chlorella-loaded poly(ionic liquid)-based microneedles (PILMN-Chl) are constructed for microacupuncture oxygen and antibacterial therapy against methicillin-resistant Staphylococcus aureus (MRSA)-infected chronic diabetic wounds. The PILMN-Chl can stably and continuously produce oxygen for more than 30h due to the photosynthesis of the loaded self-supported Chlorella. By combining the barrier penetration capabilities of microneedles, the continuous and sufficient oxygen supply of Chlorella, and the sterilization activities of PIL, the PILMN-Chl can accelerate chronic diabetic wounds in vivo by topical targeted sterilization and hypoxia relief in deep parts of wounds. Thus, the self-oxygen produced microneedles modality may provide a promising and facile therapeutic strategy for treating chronic, hypoxic, and infected diabetic wounds.

Sulfated chitosan rescues dysfunctional macrophages and accelerates wound healing in diabetic mice

Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds

Background: Wound healing relies on a balance between extracellular matrix remodelling by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Among all the MMPs, elevated MMP-9 levels are implicated in chronic wounds including diabetic ulcers, making it a potential biomarker to predict wound healing. This in turn can help determine the need for aggressive wound care management. However, most studies used invasive sampling methods like wound fluid or tissue biopsy limiting clinical implementation. Hence, this study assessed the correlation between serum levels of MMP-9 in diabetic and non-diabetic chronic wounds to explore if non-invasive methods could be used to predict healing in diabetic chronic wounds.Objective: This study aimed to compare serum MMP-9 levels in diabetic vs. non-diabetic chronic wounds, assess correlations with glycemic control (glycated hemoglobin (HbA1c)), and determine the potential of serum MMP-9 as a predictor of healing in diabetic chronic wounds.Methods: This was a cross-sectional study involving 40 patients (20 diabetics, 20 non-diabetics) with chronic wounds. Serum MMP-9 levels were measured from blood samples (avoiding invasive methods) using an enzyme-linked immunosorbent assay (ELISA). HbA1c levels were obtained for patients with diabetes mellitus. Statistical analysis compared means (t-test) and correlations (Pearson's).Results: Patients with diabetes mellitus had significantly higher serum MMP-9 (mean 21.22 ng/ml) in comparison to non-diabetics (17.35 ng/ml; p=0.0023). When compared to only 5% (one out of 20) of non-diabetics, about 75% (15 out of 20) of diabetics had MMP-9 greater than 20 ng/ml. However, no correlation was found between MMP-9 and HbA1c levels (p>0.05) among diabetic patients.Conclusions: Serum MMP-9 is elevated in diabetic chronic wounds, supporting its role as a non-invasive biomarker. Several studies have established wound fluid/tissue MMP-9 as a predictor of healing in diabetic ulcers, and this study suggests that serum MMP-9 levels could be used as a non-invasive biomarker in place of cumbersome methods. However, the lack of association of MMP-9 with HbA1c suggests glycemic control alone may not regulate MMP-9. Targeting MMP-9 inhibition (e.g., via microRNAs) could be a therapeutic strategy, warranting further research.

A sprayable TQ/Ce6@SAB/F-gel for accelerating wound healing via hypoxia-tolerant photodynamic therapy and immune-metabolic pathway.

45S5 Bioglass® works synergistically with siRNA to downregulate the expression of matrix metalloproteinase-9 in diabetic wounds

Diabetic chronic wounds and amputations are very serious complications of diabetes mellitus (DM) that result from an integration factor, including oxygen deprivation, elevated reactive oxygen species (ROS), reduced angiogenesis, and microbial invasion. These causative factors lead to tenacious wounds in an inflammatory state, which eventually results in tissue aging and necrosis. Wound healing in DM potentially targets C-X-C chemokine receptor type 4 (CXCR4) regulates several signalling pathways. The CXCR4 signalling pathway integrated with phospholipase C (PLC)/protein kinase-C (PKC) Ca2+ pathways, stromal cell-derived factor-1 (SDF-1), and mitogen- activated protein kinases (MAPKs) pathway for enhancing cell chemotaxis, proliferation, and survival. The dysregulated CXCR4 pathway is connected with poor wound healing in DM patients. Therapeutic strategies targeting CXCR4-based molecules such as UCUF-728, UCUF-965, and AMD3100 have been shown to enhance diabetic wound healing by altering miRNA expression, promoting angiogenesis, and accelerating wound closure. This study indicates that CXCR4 participation in various signalling pathways makes it essential for understanding the healing of diabetic wounds. Using specific compounds to target CXCR4 offers a potentially effective treatment strategy to improve wound healing in diabetes. Our understanding of CXCR4 signalling and its regulation processes will enable us to develop more potent wound care solutions for diabetic chronic wounds. This report concludes that CXCR4's potential therapeutic targeting shows improvements in diabetic wound repair. This review will demonstrate that CXCR4 plays a major role in wound healing through its various signalling pathways. Targeting CXCR4 with certain agonist molecules shows a therapeutic approach to potentially increasing wound healing in diabetes. By enhancing our understanding of the CXCR4 signalling mechanism in future studies, we can develop more potential treatments for chronic diabetic wounds.

Diabetic chronic wound is one of the most serious complications of diabetes, imposing enormous socioeconomic burdens on diabetic patients, their families, and society due to its refractory nature. MicroRNAs (miRNAs) have emerged as important regulators of various physiological and pathological processes. Abnormalities arise in the regulatory functions of miRNAs in chronic diabetic wounds. Therefore, the modification of miRNAs expression in diabetic wounds is an important channel for the improvement of wound healing. The clinical translation of miRNA-based therapy may become a prospective direction of diabetic wound healing. However, miRNA-based therapy is still in its early stage of development, and actual translation into clinical application will take a long time. Herein, we summarized the latest research findings on miRNAs in diabetic chronic wounds healing.

Background. Chronic diabetic foot wounds and ulcers are serious complications of the course of diabetes mellitus (DM), which account for 85% of purulent-necrotic lesions of the lower extremities. Pathogenetic mechanisms of "chronization" of wounds in the form of hyperglycemia, neuropathy, and existing infection lead to metabolic disorders in the form of tissue hypoxia and activation of matrix metalloproteinase (MMP) proteolytic enzymes. Aim: to study the role of autologous plasminogen on healing processes in diabetic wounds by modulating MMP activity. Materials and methods. 45 patients with chronic diabetic wounds, who were divided into 2 groups, participated in the study. Patients of the control group (n=25) were treated according to standard methods. Autologous plasminogen applications were used for treatment in 20 patients of the main group. Results. On the 18th day of treatment, a 3.5-fold decrease in the activity of MMP-2,-9 and complete healing of wounds was noted in 16 patients. In 4 patients, the wound defects were closed by the method of autodermoplasty with complete engraftment of grafts. In the patients of the control group, the level of MMP activity remained stably high throughout the observation period. Conclusions. The use of applications of autologous plasminogen allows to modulate the activity of MMP and create favorable conditions for the healing of chronic diabetic wounds.

Bioprinted dressing with symbiotic microbes for oxygen supply and antibacterial therapy for enhanced diabetic wound healing.

With the global prevalence of type 2 diabetes mellitus steeply rising, instances of chronic, hard-healing, or non-healing diabetic wounds and ulcers are predicted to increase. The growing understanding of healing and regenerative mechanisms has elucidated critical regulators of this process, including key cellular and humoral components. Despite this, the management and successful treatment of diabetic wounds represents a significant therapeutic challenge. To this end, the development of novel therapies and biological dressings has gained increased interest. Here we review key differences between normal and chronic non-healing diabetic wounds, and elaborate on recent advances in wound healing treatments with a particular focus on biological dressings and their effect on key wound healing pathways.

Ischemia is one of the main epidemic factors and characteristics of diabetic chronic wounds, and exerts a profound effect on wound healing. To explore the mechanism of and the cure for diabetic impaired wound healing, we established a type 2 diabetic rat model. We used an 8weeks high fat diet (HFD) feeding regimen followed by multiple injections of streptozotocin (STZ) at a dose of 10mg/kg to induce Wister rat to develop type 2 diabetes. Metabolic characteristics were assessed at the 5th week after the STZ injections to confirm the establishment of diabetes mellitus on the rodent model. A bipedicle flap, with length to width ratio 1.5, was performed on the back of the rat to make the flap area ischemic. Closure of excisional wounds on this bipedicle flap and related physiological and pathological changes were studied using histological, immunohistochemical, real time PCR and protein immunoblot approaches. Our results demonstrated that a combination of HFD feeding and a low dose of STZ is capable of inducing the rats to develop type 2 diabetes with noticeable insulin resistance, persistent hyperglycemia, moderate degree of insulinemia, as well as high serum cholesterol and high triglyceride levels. The excision wounds on the ischemic double pedicle flap showed deteriorative healing features comparing with non-ischemic diabetic wounds, including: delayed healing, exorbitant wound inflammatory response, excessive and prolonged ROS production and excessive production of MMPs. Our study suggested that HFD feeding combined with STZ injection could induce type 2 diabetes in rat. Our ischemic diabetic wound model is suitable for the investigation of human diabetic related wound repair; especically for diabetic chronic wounds.

Bionic sulfated glycosaminoglycan-based hydrogel inspired by snail mucus promotes diabetic chronic wound healing via regulating macrophage polarization