Multifunctional Nanofibrous Membranes Enhance Diabetic Wound Healing by Inhibiting Endothelial Pyroptosis and Regulating Macrophage Polarization

Peptide loaded self-healing hydrogel promotes diabetic skin wound healing through macrophage orchestration and inflammation inhibition.

An injectable and adaptable system for the sustained release of hydrogen sulfide for targeted diabetic wound therapy by improving the microenvironment of inflammation regulation and angiogenesis.

Conductive hydrogel dressings based on cascade reactions with photothermal effect for monitoring and treatment of diabetic wounds

Diabetic wounds, due to severe vascular dysfunction, persistent inflammatory responses, and susceptibility to microbial infections, exhibit delayed healing and pose a significant challenge to human health. Diabetic wounds face delayed healing and significant health challenges due to vascular dysfunction, persistent inflammation, and infection susceptibility. Therefore, the development of drugs with antibacterial capabilities, as well as the ability to effectively regulate inflammation and promote angiogenesis, is of great importance. In this study, a novel antibacterial peptide (named MYR-DM-ANG1-7) was designed. It is composed of the coassembly of myristoylated antibacterial peptide cathelicidin-DM and angiotensin 1-7 (ANG 1-7). This novel antibacterial peptide demonstrates antibacterial activity against both Escherichia coli and Staphylococcus aureus bacteria and can even effectively inhibit the formation of biofilms. In vitro experiments confirmed that MYR-DM-ANG1-7 can promote the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), reduce the level of oxidative stress, alleviate the increase in mitochondrial membrane potential caused by high glucose (HG) and lipopolysaccharide (LPS), and decrease the expression of proinflammatory cytokines IL-6 and TNF-α. Western blot experiments confirmed that MYR-DM-ANG1-7 activates PI3K by targeting the membrane receptor Mas, thereby activating AKT, which ultimately promotes the activation of eNOS to produce nitric oxide (NO), thereby enhancing the angiogenic capacity of HUVECs. In vivo experiments showed that the local application of MYR-DM-ANG1-7 significantly improved the healing of infected diabetic wounds in mice, including increased wound healing rate, reduced inflammatory cell infiltration, and promoted collagen fiber and blood vessel formation. In summary, this study successfully constructed a multifunctional novel self-assembling antibacterial peptide that can effectively regulate oxidative stress, inflammation, and angiogenesis to promote the repair of diabetic infected wounds. This research provides a brand new self-assembling lipopeptide therapeutic strategy for the treatment of diabetic infected wounds.

Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

Hyaluronic acid-based glucose-responsive antioxidant hydrogel platform for enhanced diabetic wound repair

A novel hydrogel loaded with plant exosomes and stem cell exosomes as a new strategy for treating diabetic wounds.

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

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to acidic conditions, reactive oxygen species (ROS), and high glucose levels in a diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammatory, and anti-oxidative activities. This triple-responsive mechanism is designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At a diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA, and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wounds. This micro-environment-triggered triple-responsive drug release provides a promising method for chronic diabetic wound healing.

Programmed modulation of inflammation in diabetic wounds via a dual-stage CuTA/RvD1 microneedle system.

Chronic diabetic wounds are characterized by a persistent inflammatory response, severe oxidative stress, and excessive proteolysis, creating an inhibitory microenvironment that impedes tissue regeneration. Recent findings indicate that regenerating family protein 3α (Reg3α) can promote keratinocyte proliferation and epidermal neogenesis, while also exhibiting antimicrobial properties. However, the low bioavailability significantly limits the clinical use of Reg3α in the treatment of chronic diabetic wounds. This study presents a glucose and ROS dual-responsive hydrogel loaded with Reg3α, which is synthesized by phenylboronic acid-modified hyaluronic acid (HAP) and polyvinyl alcohol (PVA). The Reg3α-loaded hydrogel (HAP-PVA/Reg3α), which exhibits favorable viscoelastic properties to adapt to wound application, promotes cell proliferation and demonstrates antibacterial and anti-inflammatory activities without inducing cytotoxicity or hemolysis in vitro. In diabetic mice, HAP-PVA/Reg3α effectively accelerates Staphylococcus aureus (S. aureus)-infected wound healing by alleviating bacterial infection, reducing inflammation, and facilitating collagen deposition. The result of RNA-seq suggests a negative regulation of M0 macrophages in the HAP-PVA/Reg3α group, which is presumably associated with their transformation into anti-inflammatory M2 macrophages. Meanwhile, serum pro-inflammatory IL-6 level is significantly decreased in Reg3α and HAP-PVA/Reg3α groups. In conclusion, HAP-PVA/Reg3α as a multifunctional hydrogel has significant potential for the treatment of chronic infected 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.

The accumulation of reactive oxygen species (ROS) in diabetic wounds leads to inflammation and impaired neovascularization. Recent studies have indicated that carbon dot nanozymes (C-dots) exhibiting superoxide dismutase (SOD)-like activity can neutralize excessive ROS and mitigate diseases associated with oxidative stress. Our study was designed to evaluate the therapeutic impact of C-dots on the healing of diabetic wounds and to unravel the complex molecular mechanisms through which these nanozymes modulate oxidative stress and inflammatory responses within the wound microenvironment. We synthesized C-dots from carbon fiber and confirmed their structure using transmission electron microscopy. The presence of carbon-carbon double bonds on the C-dots was verified with X-ray photoelectron spectroscopy. We assessed the scavenging capacity of C-dots for superoxide anion, hydroxyl radical, and nitric oxide radical using electron spin resonance spectroscopy. Their SOD-like activity and total antioxidant capacity were evaluated with commercial assay kits. In vitro experiments showed that C-dots effectively scavenged excessive ROS, protecting human keratinocytes, vascular endothelial cells, and fibroblasts from oxidative stress-induced damage. Concurrently, C-dots increased the migratory capacity of fibroblasts. In a streptozocin-induced diabetic mice model, C-dots application enhanced skin wound healing, evidenced by accelerated re-epithelialization and orderly collagen matrix assembly. Mechanistic investigations indicated that C-dots markedly suppressed ROS generation and diminished the levels of inflammatory cytokines in the wound environment. Additionally, C-dots induced an M2 polarization phenotype in macrophages and promoted neovascularization, indicating a transition from the inflammatory to the proliferative phase. Quantitative proteomic analysis was conducted to further clarify the underlying mechanisms of C-dots in ameliorating diabetic wounds. C-dots represent a robust nanomaterial-based strategy for treating diabetic wounds, with the ability to accelerate healing by alleviating oxidative stress, mitigating harmful inflammatory responses, and fostering angiogenesis. This highlights their significant therapeutic potential in the field of biomedicine.

Formononetin enhances angiogenesis in diabetic wounds by inhibiting ferroptosis through suppression of mtROS-mediated xCT/GPX4 upregulation.

Methylglyoxal deteriorates macrophage efferocytosis in diabetic wounds through ROS-induced ubiquitination degradation of KLF4.