Challenges and Advancements in Formulations for Diabetic Wound Healing - A Review

Diabetes mellitus (DM) often leads to wound healing complications, partly attributed to the accumulation of advanced glycosylation end products (AGEs) that impair fibroblast function. Far Upstream Element Binding Protein 1 (FUBP1) regulates cell proliferation, migration, and collagen synthesis. However, the impact of FUBP1 on diabetic wound healing remains unknown. This study is designed to explore the function and mechanisms of FUBP1 in diabetic wound healing. Eighteen Sprague-Dawley rats (weighing 220-240g) were randomly assigned to three groups (n = 6): a control group (NC) of healthy rats, a model group (DM) of untreated diabetic rats, and a treatment group (DM + FUBP1) of diabetic rats accepting FUBP1 treatment. A 10mm diameter circular full-thickness skin defect was created on the back of each rat. On days 1 and 7, rats in the treatment group received local injections of 5µg FUBP1 protein at the wound site, whereas the control group and model group were administered saline. Wound healing was documented on days 0, 3, 7, 10, and 14, with tissue samples from the wound areas collected on day 14 for histological analysis, including H&E staining, Masson's trichrome staining, and immunohistochemistry. Western blot analysis was utilized to assess the expression of GSK-3β, Wnt3a, and β-catenin. In vitro, the effects of various concentrations of AGEs on cell viability and FUBP1 expression were examined in human dermal fibroblasts (HDF). Cells were genetically modified to overexpress FUBP1 using lentiviral vectors and were cultured for 48h in media with or without AGEs. The impacts on fibroblast proliferation, migration, and Wnt/β-catenin signaling were evaluated using CCK-8, scratch assays, and Western blot analysis. Animal investigation revealed that from day 7 onwards, the wound healing rate of the treatment group was higher than that of the model group but lower than the control group. On day 14, the wound healing rates were as follows: control group (0.97 ± 0.01), model group (0.84 ± 0.03), and treatment group (0.93 ± 0.01). These differences were statistically significant. Histological analysis indicates that FUBP1 promotes granulation tissue formation, re-epithelialization, and collagen deposition in treatment group. Additionally, FUBP1 protein expression decreased in dermal fibroblasts when exposed to AGEs. Overexpression of FUBP1 significantly enhanced fibroblast proliferation and migration, activating the Wnt/β-catenin pathway and mitigating the inhibitory effects of AGEs. Our results suggest that FUBP1 can be a promising therapeutic target for diabetic wound healing, potentially counteracting the detrimental effects of AGEs on dermal fibroblasts through the Wnt/β-catenin pathway.

A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation

Nitric oxide (NO), a gaseous free radical, is a key signaling molecule in the different phases of the normal wound healing process. The beneficial effects of NO in wound healing are related to its antibacterial properties, regulation of inflammatory response, stimulation of proliferation and differentiation of keratinocytes and fibroblasts, and promotion of angiogenesis and collagen deposition. NO deficiency is an important mechanism responsible for poor healing in diabetic wounds. In this chapter, the function of NO in diabetic wound healing and the possible therapeutic significance of NO in the treatment of diabetic wounds are discussed. Current knowledge supports this notion that NO-based intervention is a promising therapeutic approach for diabetic wound healing.

Long-term diabetes can cause many serious complications. It is generally accepted that diabetes results in the development of diabetic cardiomyopathy independent of hypertension and coronary heart disease. Cardiac fibrosis is...

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.

Near-infrared light-responsive multifunctional hydrogel releasing peptide-functionalized gold nanorods sequentially for diabetic wound healing

Diabetic foot ulceration (DFU) is a chronic complication of diabetes that is characterized by impaired wound healing in the lower extremities. DFU remains a major clinical challenge because of poor understanding of its pathogenic mechanisms. Impaired wound healing in diabetes is characterized by decreased angiogenesis, reduced bone marrow-derived endothelial progenitor cell (EPC) recruitment, and decreased fibroblast and keratinocyte proliferation and migration. Recently, increasing evidence has suggested that increased hypoxic conditions and impaired cellular responses to hypoxia are essential pathogenic factors of delayed wound healing in DFU. Hypoxia-inducible factor-1 (HIF-1, a heterodimer of HIF-1α and HIF-1β) is a master regulator of oxygen homeostasis that mediates the adaptive cellular responses to hypoxia by regulating the expression of genes involved in angiogenesis, metabolic changes, proliferation, migration, and cell survival. However, HIF-1 signalling is inhibited in diabetes as a result of hyperglycaemia-induced HIF-1α destabilization and functional repression. Increasing HIF-1α expression and activity using various approaches promotes angiogenesis, EPC recruitment, and granulation, thereby improving wound healing in experimental diabetes. The mechanisms underlying HIF-1α regulation in diabetes and the therapeutic strategies targeting HIF-1 signalling for the treatment of diabetic wounds are discussed in this review. Further investigations of the pathways involved in HIF-1α regulation in diabetes are required to advance our understanding of the mechanisms underlying impaired wound healing in diabetes and to provide a foundation for developing novel therapeutic approaches to treat DFU.

ABSTRACTDelayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small‐molecule drugs represent a highly promising therapeutic strategy. This study aims to evaluate the therapeutic efficacy of ellagic acid‐encapsulated small extracellular vesicles (EA‐sEVs) in diabetic wound regeneration and to unravel related mechanisms. Cytotoxicity tests of ellagic acid (EA) as liposomal small molecules (LSMs) were performed with the CCK8 assay. EA was incorporated into sEVs obtained from chorionic plate‐mesenchymal stem cells (CP‐MSCs) to construct EA‐engineered sEVs. The protective effects of EA‐sEVs on human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) induced by high glucose (HG) were assessed through the evaluation of their proliferative, migrative and differentiative capabilities. Furthermore, to illustrate the underlying mechanism, the specific biological targets of EA were predicted and confirmed. Finally, EA‐sEVs were encapsulated in GelMA hydrogel for investigating the pro‐healing effects on diabetic wounds. EA was harmless to cell viability, increasing the possibility and safety of drug development. EA‐engineered sEVs were fabricated by loading EA in sEVs. In vitro, EA‐sEVs promoted the proliferation, migration, and transdifferentiation of HG‐HDFs and the proliferation and migration of HG‐HEKs. Mechanism analysis elucidated that epidermal growth factor receptor (EGFR) was the specific biological target of EA. EA interacting with EGFR was responsible for the functional improvement of HG‐HDFs and HG‐HEKs. In vivo, EA‐sEVs encapsulated in GelMA promoted the healing of diabetic wounds by improving re‐epithelialisation, collagen formation and the expression of EGFR. Gel‐EA‐sEVs promoted diabetic wound healing by improving biological functions of HDFs and HEKs. EGFR was first identified as the specific biological target of EA and was responsible for the functional improvement of HG‐HDFs and HG‐HEKs by Gel‐EA‐sEVs. Hence, Gel‐EA‐sEVs can serve as a new promising active dressing for diabetic wound treatment.

Dual-drug loaded polysaccharide-based self-healing hydrogels with multifunctionality for promoting diabetic wound healing

Diabetic foot wound healing is a major clinical problem due to impaired angiogenesis and bacterial infection. Therefore, an effective regenerative dressing is desiderated with the function of promoting revascularization and anti-bacteria. Herein, a multifunctional injectable composite hydrogel was prepared by incorporation of the cerium-containing bioactive glass (Ce-BG) into Gelatin methacryloyl (GelMA) hydrogel. The Ce-BG was synthesized by combining sol-gel method with template method, which maintained spherical shape, chemical structure and phase constitution of bioactive glass (BG). The Ce-BG/GelMA hydrogels had good cytocompatibility, promoted endothelial cells migration and tube formation by releasing Si ion. In vitro antibacterial tests showed that 5 mol % CeO2-containing bioactive glass/GelMA (5/G) composite hydrogel exhibited excellent antibacterial properties. In vivo study demonstrated that the 5/G hydrogel could significantly improve wound healing in diabetic rats by accelerating the formation of granulation tissue, collagen deposition and angiogenesis. All in all, these results indicate that the 5/G hydrogel could enhance diabetic wound healing. Therefore, the development of multifunctional materials with antibacterial and angiogenic functions is of great significance to promote the repair of diabetic wound healing.

BackgroundDiabetic cutaneous ulcers (DCU) are a complication of diabetes with diabetic foot ulcers being the most common, and the wounds are difficult to heal, increasing the risk of bacterial infection. Cell-based therapy utilizing mesenchymal stem cells (MSCs) is currently being investigated as a therapeutic avenue for both chronic diabetic ulcers and severe burns. Wharton’s jelly mesenchymal stem cell (WJMSC) with PF-127 hydrogel and sodium ascorbyl phosphate (SAP) improved skin wound healing in mice. Whether this combination strategy is helpful to diabetic ulcers wound healing remains to be explored.MethodsFirstly, the WJMSCs embedded in PF-127 and SAP combination were transplanted onto excisional cutaneous wound bed in type 2 diabetic Sprague Dawley (SD) rats. Two weeks after transplantation, the skin tissue was collected for histological and immunohistochemical analysis. Further, overexpressing-EGFP WJMSCs were performed to investigate cell engraftment in the diabetic cutaneous ulcer. The apoptosis of WJMSCs which encapsulated with combination of PF-127 and SAP was detected by TUNEL fluorescence assay and RT-PCR in vitro. And the mitochondrial damage induced by oxidative stress assessed by MitoTracker and CMH2DCFDA fluorescence assay.ResultsIn diabetic cutaneous wound rat model, PF-127 plus SAP-encapsulated WJMSCs transplantation promoted diabetic wound healing, indicating improving dermis regeneration and collagen deposition. In diabetic wound healing, less pro-inflammatory M1 macrophages, more anti-inflammatory M2 tissue-healing macrophages, and neovascularization were observed in PF-127 + SAP + WJMSCs group compared with other groups. SAP supplementation alleviated the apoptosis ratio of WJMSCs embedded in the PF-127 in vitro and promoted cell survival in vivo.ConclusionPF-127 plus SAP combination facilitates WJMSCs-mediated diabetic wound healing in rat through promoting cell survival, the macrophage transformation, and angiogenesis. Our findings may potentially provide a helpful therapeutic strategy for patients with diabetic cutaneous ulcer.

The treatment of diabetic chronic wounds is still faced with great challenges, mainly due to wound infection, excessive inflammation, and peripheral vascular disease in the wound area. Therefore, it is of great importance to develop a novel multifunctional hydrogel with high efficiency to accelerate diabetic wound healing. Curcumin (Cur), a Chinese herbal, has shown great potential in enhancing the healing of diabetic chronic wounds because of its immunomodulatory and pro-angiogenic properties. However, its low aqueous solubility, poor bioavailability, and chemical instability have limited its clinical applications. To address these current bottlenecks, novel poly(vinyl alcohol) (PVA)-chitosan (CS)/sodium alginate (SA)-Cur (PCSA) hydrogels were prepared for the first time, and they demonstrated all of the above intriguing performances by the Michael addition reaction of CS and Cur. PCSA hydrogels show multiple dynamic bonds, which possess strong mechanical properties (tensile stress: ∼0.980 MPa; toughness: ∼258.45 kJ/m3; and compressive strength: ∼7.38 MPa at strain of 80%). These intriguing performances provided an optimal microenvironment for cell migration and proliferation and also promoted the growth of blood vessels, leading to early angiogenesis. Importantly, the experimental results demonstrated that PCSA hydrogels can effectively transform pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages without the need for additional ingredients in vitro. Benefiting from these characteristics, a full-thickness diabetic wound in a rat model demonstrated that PCSA hydrogels can effectively accelerate wound healing via ROS-scavenging, downregulation of IL-1β, and upregulation of CD31 expression, resulting in angiogenesis and collagen deposition. This strategy not only provides a simple and safe Cur-based hydrogel for diabetic wound healing but also highlights the significant potential for the development of high-performance biomaterials for promoting diabetic wound healing using traditional Chinese medicine.

The effects of estradiol and progesterone on the synthesis of collagen in tracheal surgery

Background: Diabetic foot ulcer (DFU) is a prevalent complication of diabetes. Current therapeutic options remain inadequate in controlling its progression. Objectives: To evaluate the wound-healing potential of zofenopril (ZOF) and fisetin (FS) in a rat model of DFU. Methods: Sixty-five rats were included in the study and divided into 7 groups: nDnW: non-diabetic, non-wounded; nDW: non-diabetic, wounded; DWC: diabetic, wounded control. Insulin, ZOF, FS, and ZOF+FS. Diabetes was induced using 60mg/kg streptozotocin (STZ), and a full-thickness excision wound was created on the dorsal surface of the hind paw. The wound size was measured by ImitoWound application. Assessment of blood glucose, C-reactive protein (CRP), interleukin-(IL)-10, total antioxidant capacity (TAOC), vascular endothelial growth factor (VEGF), and hydroxyproline was performed. Tissue samples were examined for histological changes. Results: ZOF, FS, and their combination significantly accelerated diabetic wound healing via reducing wound surface area and percentage of wound contraction, improved glycemic control, and mitigated histological alterations. They significantly reduced the serum level of CRP in the inflammatory phase and increased VEGF and hydroxyproline. Histopathological analysis revealed a reduction in inflammatory infiltration at the wound site, marked angiogenesis and fibroblast proliferation on Day 8, and moderate to excellent epidermal thickness with optimal collagen deposition on Day 16 post-wounding. Conclusions: ZOF, FS, and their combination enhanced wound healing by ameliorating inflammation, improving angiogenesis, collagen synthesis, and re-epithelization. The suggested mechanisms are anti-inflammatory, elevation of the level of VEGF and hydroxyproline, and glycemic control, thereby accelerating wound contraction and improving delayed wound healing in diabetes.

Highly absorptive dressing composed of natural latex loaded with alginate for exudate control and healing of diabetic wounds