A nano-composite hyaluronic acid-based hydrogel efficiently antibacterial and scavenges ROS for promoting infected diabetic wound healing

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

Ionic liquid-based non-releasing antibacterial, anti-inflammatory, high-transparency hydrogel coupled with electrical stimulation for infected diabetic wound healing

Herein, we propose a Carbopol hydrogel-based oxygen nanodelivery "nanohyperbaric" system as a wound dressing material for an enhanced wound healing process. Oxygen nanobubbles (ONBs) were used to supply oxygen, and collagenase was added in the gel as a drug model. Both oxygen and collagenase would benefit the wound healing process, and the Carbopol hydrogel serves as the matrix to load ONBs and collagenase in the wound dressing. The obtained ONB-embedded Carbopol hydrogel with collagenase (ONB-CC) could provide 12.08 ± 0.75 μg of oxygen from 1 mL of ONB-CC and exhibited a notable capacity to prolong the oxygen holding for up to 3 weeks and maintained the enzymatic activity of collagenase at more than 0.05 U per 0.1 mL of ONB-CC for up to 17 days. With HDFa cells, the ONB-CC did not show a notable effect on the cell viability. In a scratch assay, the oxygen from ONBs or collagenase aided cell migration; further, the ONB-CC induced the most obvious scratch closure, indicating an improvement in wound healing as a cocktail in the ONB-CC. The mRNA expression further demonstrated the effectiveness of the ONB-CC. Studies in rats with punched wounds treated with the ONB-CC dressing showed improved wound closure. Histopathological images showed that the ONB-CC dressing enhanced re-epithelization and formation of new blood vessels and hair follicles. The proposed ONB-CC has excellent potential as an ideal wound dressing material to accelerate wound healing by integration of multiple functions.

Corrole-based photothermal nanocomposite hydrogel with nitric oxide release for diabetic wound healing.

Efficient management of difficult-to-heal diabetic wounds remains a clinical challenge owing to bacterial infections, as well as oxidative and hyperglycemic complex pathology. Therefore, developing intelligent strategies for diabetic wound healing is urgently needed. Herein, an ultrasound (US)-responsive microneedle (MN) patch (MN@GOX@TiO2-X@CO) capable of controlled delivery of carbon monoxide (CO) gas within the skin for effective treatment of diabetic infected wounds is developed. Benefiting from the specific form of microneedle (MN) patch, sonosensitizer (TiO2-X), •OH-responsive CO prodrug (MPA-CO), and glucose oxidase (GOX) can be loaded together and effectively delivered to infectious wounds. With the semi-fluidic hyaluronic acid (HA) coating under the physiological condition, CO could be released efficiently in situ and directly acted on infected wound tissue upon US triggering. Both in vitro and in vivo results showed that US-triggered CO release from MN@GOX@TiO2-X@CO not only effectively inhibited the S. aureus and MRSA infection but also promoted fibroblasts proliferation and migration under hyperglycemic physiology, thereby accelerating diabetic wound healing. Collectively, the approach effectively addresses the impaired skin regeneration function in diabetic wounds and offers a promising therapeutic strategy for the efficient healing of infected diabetic wounds.

The angiogenic cascade is getting increasingly complex. A few years ago, vasculogenesis and angiogenesis were considered as the primary mechanisms leading to the formation of new blood vessels. The original definition of vasculogenesis denotes the formation of a primary embryonic vascular network from in situ differentiating angioblastic cells.1 In contrast, angiogenesis primarily referred to the sprouting of blood vessels from preexisting vessels.1 Recent advances in the identification of molecules that regulate angiogenesis and vascular remodeling have shown that the simplistic model of an invading capillary sprout is not sufficient to appreciate the whole spectrum of morphogenic events that are required to form a neovascular network (Figure 1).1–3 Undoubtedly, vascular endothelial growth factor (VEGF) acts at an early point in the hierarchical order of morphogenic events and probably fulfills all criteria to be considered as a master switch of the angiogenic cascade. In contrast, the angiopoietins and their receptor Tie-2 as well as the ephrins and their corresponding Eph receptors appear to act at a somewhat later stage of neovessel formation. These molecules orchestrate a number of related, yet functionally and molecularly not well understood, processes such as vessel assembly (network formation and formation of anastomoses), vessel maturation (recruitment of mural cells [pericytes and smooth muscle cells], and extracellular matrix assembly, pruning of the primary vascular bed), and acquisition of vessel identity (formation of arteries, capillaries, and veins)3,4 (Figure 2). Lastly, the mechanisms of organotypic differentiation of the vascular tree (continuous endothelium, discontinuous endothelium, fenestrated endothelium) are not at all understood and the first molecules that govern subpopulation-specific vascular growth and differentiation are just being uncovered.5,6 Figure 1. Change of paradigm. From sprouting angiogenesis to vascular morphogenesis. Basement membrane degradation, directed endothelial cell migration, and proliferation (left) were considered as the primary mechanisms of angiogenesis. …

Mussel-inspired nanocomposite hydrogel based on alginate and antimicrobial peptide for infected wound repair

3D nanocomposite alginate hydrogel loaded with pitavastatin nanovesicles as a functional wound dressing with controlled drug release; preparation, in-vitro and in-vivo evaluation

Exosome laden oxygen releasing antioxidant and antibacterial cryogel wound dressing OxOBand alleviate diabetic and infectious wound healing

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.

Dietary nitrate accelerates the healing of infected skin wounds in mice by increasing microvascular density

Hypoxia, reduced vascularization, elevated oxidative stress, and infection are critical clinical hallmarks of non-healing chronic diabetic wounds. The dataset presented here is in support of the development and evaluation of the exosome laden oxygen releasing OxOBand for treatment and management of diabetic and infectious wounds [1]. It describes the additional results in support of the development of OxOBand and its evaluation for diabetic wound healing. Exosomes were isolated from adipose-derived stem cells (ADSCs) and characterized through dynamic light scattering (DLS) and scanning electron microscopy (SEM). The encapsulation of exosomes by cells and its effect on migration of NIH3T3 cells under in-vitro condition is described. Further antioxidant polyurethane (PUAO) cryogel and oxygen releasing antioxidant (PUAO-CPO) cryogel scaffolds were fabricated as reported earlier [2,3] and NIH3T3, HaCaT and ADSCs were cultured on these scaffolds. “OxOBand”, the calcium peroxide containing oxygen releasing antioxidant polyurethane (PUAO-CPO) scaffold along with exosomes was evaluated in chronic wounds in diabetic rats. The wounds were also infected with Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa) bacteria and OxOBand was further evaluated for the healing of these infectious diabetic wounds. Interpretation of this data can be found in a research article title “Exosome laden oxygen releasing antioxidant and antibacterial cryogel wound dressing OxOBand alleviate diabetic and infectious wound healing, Shiekh et. al., Biomaterials, 2020 [1].

Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-platelet derived growth factor receptor-β (PDGFR-β) were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Fentanyl significantly promoted wound closure as compared to phosphate-buffered saline (PBS). Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho-PDGFR-β co-localized with CD31 co-staining for vasculature. Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing.

In-situ forming hydrogel incorporated with reactive oxygen species responsive and antibacterial properties for diabetic infected chronic wound healing

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.