Diabetic wounds experience a hyperglycemic, hypoxic environment, combined with ongoing oxidative stress and inflammatory imbalances, significantly disrupts normal healing process. Advanced hydrogels have been considered one of the most exciting medical biomaterials for the potential in wounds healing. Herein, a novel conductive hydrogel (HEPP), designed to release nanozyme (PTPPG) in response to its microenvironment, was created to facilitate glucose (Glu) catabolism. Furthermore, the HEPP integrates photodynamic therapy (PDT), photothermal therapy (PTT), and self-cascading reactive oxygen species (ROS) to prevent bacterial infections while ensuring a continuous supply of oxygen (O2) to the wound. The HEPP not only adeptly controls high ROS levels, but also enhances the regulation of inflammation in the wound area via electrical stimulation (ES), thereby promoting healing that is supported by the immune response. Studies conducted in vitro, along with transcriptomic analyses, indicate that ES primarily mitigates inflammation by regulating Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The effects of HEPP combined with ES are primarily connected to their impact on TNF signaling pathways. By reducing the formation of ROS and employing ES to effectively lessen inflammation, this approach offers an innovative method to manage complicated diabetic wounds, ulcers, and a range of inflammatory conditions linked to infections.

Diabetic foot ulcers (DFUs), a common and serious complication of diabetes mellitus, are exacerbated by hyperglycemia-induced chronic inflammation and oxidative stress, which collectively impede the wound-healing process. Effective management requires coordinated regulation of the pathological microenvironment through localized glucose reduction, anti-inflammatory modulation, and reactive oxygen species (ROS) scavenging. This study developed an injectable functionalized hydrogel incorporating a Bi nanocrystal-decorated bismuth tungstate/hydrogen-doped titanium dioxide (Bi2WO6/H-TiO2) heterojunction with dual photocatalytic properties: glucose degradation and hydrogen evolution. Upon exposure to light, the hydrogel exploits glucose in the wound as the sacrificial substrate to simultaneously decrease local glucose concentrations and facilitate in situ hydrogen production. The released hydrogen exhibits potent antioxidant and anti-inflammatory activities, synergizing with glucose consumption to inhibit cellular apoptosis and accelerate tissue repair. A systematic evaluation revealed enhanced cell proliferation and migration in hyperglycemic in vitro models. In vivo experiments using a diabetic murine model demonstrated 50 % wound closure within 3 days, accompanied by improved angiogenesis and collagen remodeling. This photocatalytic synergistic strategy represents a clinically promising modality for diabetic wound treatment by regulating the microenvironment and restoring redox homeostasis.

The study aims to assess whether a radiation-crosslinked carboxymethyl-chitosan/gelatin hydrogel can exhibit superior healing properties in diabetic wounds through collagen synthesis, epithelial maturation, inflammation regulation and angiogenesis, and determine if it can be applied on alternate days to reduce patient compliance pressure.

The study used a full-thickness diabetic wound rat model. The hydrogel was applied either daily or on alternate days. H&E, Masson's trichrome, Sirius red and immunohistochemical staining were employed. Two patients with diabetes were recruited for case studies where the hydrogel was applied on alternate days.

Under the application of the hydrogel, accelerated healing was observed, with enhanced re-epithelialization and dermal differentiation. The treated groups developed mature skin characteristics absent in the control group, and a well-organized collagen network was observed. There was also accelerated macrophage infiltration, phenotype shift and enhanced angiogenesis at different healing stages. In addition, two patients were positive with alternate-day application of the hydrogel.

The radiation-crosslinked carboxymethyl-chitosan/gelatin hydrogel shows great potential as a promising modality for diabetic wound management, with both daily and alternate-day applications having immunomodulatory and pro-angiogenic functions.

Objective: To evaluate the clinical efficacy of combining an offloading device with a contralateral shoe lift to compensate for induced limb-length discrepancies in participants with plantar diabetes-related foot ulcers. Approach: Between March 2021 and December 2023, 42 consecutive patients with active plantar diabetic foot ulcers (DFUs) were randomly assigned (1:1) to the treatment group (limb-length discrepancy compensation with a shoe lift in the therapeutic footwear of the contralateral limb) or a control group that did not receive limb-length discrepancy compensation. Primary outcomes included the 20-week wound-healing rate and wound area reduction. Secondary outcomes included minor amputation, new ulcers in the contralateral limb, perceived comfort, and hip pain. Results: On an intention-to-treat basis, 15 participants in the control and 19 in the treatment group showed ulcer healing (p = 0.0023). In those with >80% adherence to the offloading device, multivariate analysis showed that the shoe lifts improved ulcer healing time. The use of a shoe lift reduced the number of minor amputations and the occurrence of new ulcers in the contralateral limb (p = 0.035; p = 0.033 respectively). Hip pain and perceived comfort improved with the use of shoe lifts (p < 0.001). Innovation: It validates the use of shoe lifts for patients with DFUs, as it is the first largest study of its kind to establish a clear reference standard to guide clinician decision-making. Conclusion: The use of shoe lifts reduced healing time in participants with diabetes and active plantar foot ulcers. Shoe lifts reduce late complications, including new ulcers in the contralateral limb and minor amputations.

Diabetic foot ulcers (DFUs) are a severe complication of diabetes, often leading to amputation. Hyperglycemia induced nerve and vascular damage significantly increases DFU risk. The advent of 3D printing technology presents a revolutionary concurrently address glycemic control and wound management, potentially improving patient adherence and offering a more holistic treatment strategy.

This article reviews current oral antidiabetic medications and explores the potential of innovative 3D printing technology to develop extended release tablets in two distinct release profiles. Additionally, it investigates the application of this technology in creating novel wound dressing solutions aimed at facilitating DFU healing. .

The integration of 3D printing technology enables the production of customized, extended-release oral medications that optimize glycemic control while minimizing fluctuations in blood sugar levels. Furthermore, 3D-printed wound dressings demonstrate promising potentialfor enhancing wound healing by providing personalized structural support and controlled drug delivery.

A multidisciplinary approach that integrates advanced wound care and diabetes management is crucial to address the escalating challenges posed by DFUs. Leveraging3D printing technology to develop sustained-release medications and innovative wound dressingsmay significantly improve DFU outcomes and improve the quality of life for individuals with diabetes.

Diabetes mellitus (DM) is a chronic metabolic disorder marked by sustained hyperglycemia. These disturbances contribute to extensive damage across various tissues and organs, giving rise to severe complications such as vision loss, kidney failure, amputations, and higher morbidity and mortality rates. Furthermore, DM imposes a substantial economic and emotional burden on patients, families, and healthcare systems. Mitophagy, a selective process that targets the clearance of damaged or dysfunctional mitochondria, is pivotal for sustaining cellular homeostasis through mitochondrial turnover and recycling. Emerging evidence indicates that dysfunctional mitophagy acts as a key pathogenic driver in the pathogenesis of DM and its associated complications. Natural small molecules are particularly attractive in this regard, offering advantages such as low toxicity, favorable pharmacokinetic profiles, excellent biocompatibility, and a broad range of biochemical activities. This review systematically evaluates the mechanistic roles of natural small molecules-including ginsenosides, resveratrol, and berberine-in enhancing mitophagy and restoring mitochondrial homeostasis via activation of core signaling pathways (e.g., PINK1/Parkin, BNIP3/NIX, and FUNDC1). These pathways collectively ameliorate pathological hallmarks of DM, such as oxidative stress, chronic inflammation, and insulin resistance. Furthermore, the integration of nanotechnology with these compounds optimizes their bioavailability and tissue-specific targeting, thereby establishing a transformative therapeutic platform for DM management. Current evidence demonstrates that mitophagy modulation by natural small molecules not only offers novel therapeutic strategies for DM and its chronic complications but also advances the mechanistic foundation for future drug development targeting metabolic disorders.

Effective modulation of persistent inflammation is crucial for chronic wound healing. However, the interaction cascade between inflammatory factors and immune cells at the soft-tissue wound interface poses an incredible challenge for this purpose. Here, we report an immunosuppressive pure DNA hydrogel (Is-pDNAgel) that reprograms inflammatory responses from both molecular and cellular dimensions. Specifically, high-density negative charges enable Is-pDNAgel to efficiently scavenge free chemokines, mitigating neutrophil and macrophage infiltration. Moreover, its immunosuppressive domain synergistically acts on activated residual immune cells and suppresses multiple proinflammatory signaling pathways, thereby creating a positive circuit to boost anti-inflammatory efficacy. Is-pDNAgel can further facilitate migration and proliferation of endogenous endothelial cells owing to its intrinsic extracellular matrix-mimicking structure, promoting re-epithelialization and neovascularization for tissue regeneration without additional bioactive components. Such an "all-in-one" hydrogel outperforms a commercial dressing to accelerate the healing of chronic wounds in a diabetic mouse model, offering a valuable tool for developing regenerative medicine.

Long-term inflammation and impaired angiogenesis are thought to be the causes of delayed healing or nonhealing of diabetic wounds. S100A12 is an essential pro-inflammatory factor involved in inflammatory reactions and serves as a biomarker for various inflammatory diseases. However, whether high level of S100A12 exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that the serum concentration of S100A12 is significantly elevated in patients with type 2 diabetes. Exposure of stratified epidermal cells to high glucose environment led to increased expression and secretion of S100A12, resulting in impaired endothelial function by binding to the advanced glycation endproducts (RAGE) or Toll-like receptor 4 (TLR4) on endothelial cell. The transcription factor Krüpple-like Factor 5 (KLF5) is highly expressed in the epidermis under high glucose conditions, activating the transcriptional activity of the S100A12 and boost its expression. By establishing diabetic wounds model in alloxan-induced diabetic rabbit, we found that local inhibition of S100A12 significantly accelerated diabetic wound healing by promoting angiogenesis. Our results illustrated the novel endothelial-specific injury function of S100A12 in diabetic wounds and suggest that S100A12 is a potential target for the treatment of diabetic wounds.

Chronic pain in the diabetic foot (DF) is a common complication of diabetes, bringing a significant burden to patients, their families, and even society. There is no very effective treatment for it, traditional treatments such as medication, lumbar sympathetic nerve block, and alternative therapies are often not very effective and have more adverse effects. The emergence of neuromodulation technology has brought new hope for the treatment of DF, among which spinal cord stimulation (SCS) is a hotspot in current research and has achieved remarkable efficacy in the study of DF treatment by blocking pain signaling and improving circulation and other mechanisms. This article reviews the SCS technique and clinical trails of SCS for chronic DF pain, and describes the prospects and current challenges of SCS.

Patients with diabetic foot ulcers (DFU) suffering from severe lower limb ischemia face the risk of amputation. Concomitant oxidative stress and hyperinflammation commonly manifest within the tissue affected by DFU, exacerbating the deterioration of DFU wounds. One-two punch strategy of anti-oxidative damage plus anti-inflammatory is anticipated to tackle the challenge of non-healing diabetic wounds. Here, we introduced a dual-approach treatment strategy involving the probiotic Weissella cibaria (WC) modified with desferrioxamine (DFO). This engineered probiotic, known as WC@DPA, aims to ameliorate oxidative stress within the ischemic microenvironment and stimulate the formation and proliferation of endothelial tubular structures. When applied with chronic wounds and ischemic hindlimb injuries in diabetic mice, WC@DPA gel demonstrated an effective performance in modulating oxidative damage, reducing local vascular inflammation, and facilitating muscle tissue repair and vascular reconstruction. We believe that our engineered probiotic represents a promising therapeutic avenue for managing ischemic injuries associated with DFU.

Diabetic foot ulcers (DFUs) are prevalent among individuals with poorly controlled diabetes, and severe cases can result in increased morbidity and a poor quality of life. This study aimed to identify the factors that affect the severity of DFUs, offering insights into potential interventions that could enhance patient outcomes.

A prospective cross-sectional study was conducted from August 2023 to March 2024 at Muhimbili National Hospital in Tanzania, involving 177 consecutively selected patients with DFUs. The primary outcome variable was the severity of DFUs, which was assessed using the Meggitt-Wagner severity score. Both socio-demographic and clinical characteristics were evaluated to determine their association with the outcome variable using multivariate ordinal logistic regression analysis.

The median age of the study participants was 60 years (IQR = 52-68), with a male-to-female ratio of 2 to 1. Notably, Wagner grades 4 and 5 accounted for 57.6% of the participants. Factors associated with increased severity of DFUs included age over 60 years (aOR = 1.83, 95% CI 1.05-3.23, p = 0.035) and poor adherence to diabetes medications (aOR = 2.62, 95% CI 1.36-5.09, p = 0.004). Conversely, having health insurance coverage was linked to better outcomes (aOR = 0.51, 95% CI 0.27-0.96, p = 0.036).

The study highlights factors that can enhance comprehensive care for diabetic patients, especially elderly individuals. Key measures include implementing educational programs to encourage medication adherence, improving healthcare access, particularly for uninsured individuals, promoting insurance coverage, and making diabetes treatments more affordable.

The prevalence of diabetic foot ulcers (DFUs) is 4 to 10% among people with diabetes mellitus. DFUs are associated with increased morbidity and mortality as well as reduced quality of life and have a significant impact on overall healthcare expenditure. The main predisposing factors for DFU are diabetic neuropathy, peripheral arterial disease, and trauma. The fact that a range of tests can be used to identify patients at risk for DFU often causes confusion among practitioners regarding which screening tests should be implemented in clinical practice. Herein we sought to determine whether tests of somatic nerve function, such as pinprick sensation, thermal (cold/hot) test, ankle reflexes, vibration perception, 10-g monofilament, Ipswich touch test, neuropathy disability score, and nerve conduction studies, predict the development of DFUs. In addition, we examined whether sudomotor function screening tests, such as Neuropad, sympathetic skin response, and other tests, such as elevated plantar pressure or temperature measurements, can be used for DFU screening. If not treated properly, DFUs can have serious consequences, including amputation, early detection and treatment are vital for patient outcomes.

The high incidence and prevalence of diabetic foot ulcers (DFUs) present a substantial clinical and economic burden, necessitating innovative therapeutic approaches. Fibroblasts, characterized by their intrinsic cellular plasticity and multifunctional capabilities, play key roles in the pathophysiological processes underlying DFUs. Hyperglycemic conditions lead to a cascade of biochemical alterations that culminate in the dysregulation of fibroblast phenotype and function, which is the primary cause of impaired wound healing in DFUs. Biomaterials, particularly those engineered at the nanoscale, hold significant promise for enhancing DFU treatment outcomes. Electrospun nanofiber scaffolds, with their structural and compositional similarities to the natural extracellular matrix, serve as an effective substrate for fibroblast adhesion, proliferation, and migration. This review comprehensively summarizes the biological behavior of fibroblasts in DFUs and the mechanism mediating wound healing. At the same time, the mechanism of biological materials, especially electrospun nanofiber scaffolds, to improve the therapeutic effect by regulating the activity of fibroblasts was also discussed. By highlighting the latest advancements and clinical applications, we aim to provide a clear perspective on the future direction of DFU treatment strategies centered on fibroblast-targeted therapies.

Diabetic foot ulcer is a critical complication of diabetes, but the wound microenvironment and its healing process are not completely understood. In this study, we optimized single-cell profiling from sharp debrided ulcers. Our findings demonstrate that healing diabetic foot ulcers were significantly enriched with distinct fibroblasts-expressing genes related to inflammation (CHI3L1, IL6) and extracellular matrix remodeling (ASPN), validating our previous studies on surgically resected ulcers. The race-focused analysis depicted lower expression of key healing-associated genes such as CHIL3L1, matrix metalloproteinase 11 gene MMP11, and SFRP4 in fibroblasts of non-Hispanic Black patients than in those of White patients. In cellular communication analysis, healing-enriched fibroblasts of non-Hispanic Black patients exhibited upregulation of signaling pathways such as WNT, whereas those of White patients showed insulin-like GF and Midkine pathways upregulation. Our findings advocate race as a risk marker of diabetic foot ulcer outcomes, likely reflecting underlying disparities in environmental exposures and access to care that profoundly influence healing markers. Using sharp debrided tissues for single-cell assays, this study highlights the need for in-depth investigations into dysregulated wound healing microenvironments of under-represented racial groups.

Diabetic wound healing is a formidable challenge, often complicated by biofilms, immune dysregulation, and hindered vascularization within the wound environments. The intricate interplay of these microenvironmental factors has been a significant oversight in the evolution of therapeutic strategies. Herein, the design of an efficient and versatile oxygen-bonded amorphous transition metal dichalcogenide biocatalyst (aRuS-Or) with pH-responsive reactive oxygen biocatalysis for combined antibacterial and anti-inflammatory therapies in promoting diabetic wound healing is reported. Leveraging the incorporation of Ru─O bonds, aRuS-Or exhibits optimized adsorption/desorption behavior of oxygen intermediates, thereby enhancing both the reactive oxygen species (ROS) generation activity in acidic conditions and ROS scavenging performance in neutral environments. Remarkably, aRuS-Or demonstrates exceptional bactericidal potency within infected milieus through biocatalytic ROS generation. Beyond its antimicrobial capability, post-eradication, aRuS-Or serves a dual role in mitigating oxidative stress in inflammatory wounds, providing robust cellular protection and fostering an M2-phenotype polarization of macrophages, which is pivotal for accelerating the wound repair process. The findings underscore the multifaceted efficacy of aRuS-Or, which harmoniously integrates high antibacterial action with anti-inflammatory and pro-angiogenic properties. This triad of functionalities positions aRuS-Or as a promising candidate for the comprehensive management of complex diabetic ulcers, addressing the unmet needs in the current therapeutics.

The treatment of diabetic foot ulcers (DFUs) represents a significant challenge due to the complexity of the wound microenvironment. Several factors, including infection, inflammation, and impaired angiogenesis, can complicate the healing process and reduce the effectiveness of current clinical treatments. To address these challenges, this work develops a multifunctional sponge containing a zeolitic imidazolate framework-8/bacterial cellulose (ZIF-8/BC) matrix loaded with the antioxidant naringin (Nar). This sponge is fabricated using a straightforward method that involves in situ synthesis followed by lyophilization. The as-prepared Nar/ZIF-8/BC sponge exhibits excellent mechanical properties (e.g., tensile strength reaching 2.28 MPa), high exudate management performance (water absorption approximately 70 times), and excellent antimicrobial activity (100%). Additionally, the pH-responsive properties of ZIF-8 enable the composite sponge to release naringin in response to the DFU microenvironment. The released drug promotes angiogenesis, resulting in antioxidant and anti-inflammatory effects, which further encourage the healing of infected wounds in diabetic rats. Overall, the Nar/ZIF-8/BC sponge is a promising multifunctional dressing for DFU healing, providing an efficient solution for intractable wounds by regulating the microenvironment, which meets complex clinical demands.

Diabetic foot ulcers (DFUs) as a nonhealing wound remain a clinical challenge, and the development of pro-healing and cost-effective drugs is in urgent need. Herein, we reported a novel galactosylated glycosaminoglycan (GAG) from the snail Helix lucorum, as an effective pro-healing compound. The snail GAG is composed of a heparan sulfate-like main chain and galactose side chains at C-3 of GlcNAc residue. Its main chain has a repeating disaccharide structure of → 4)-α-D-GlcNAc-(1 → 4)-α-L-IdoA2S(1 →. This is the first example of glycosaminoglycan with galactose branches from mollusks. Pharmacological experiments showed that the H. lucorum GAG significantly promoted skin wound healing in both healthy and diabetic mice by accelerating granulation tissue regeneration, angiogenesis, and collagen deposition. The distinctive galactosylated substitution may play an important role on its pro-healing activity. Our discovery enriches the diversity of non-anticoagulant heparan sulfate-like glycosaminoglycans, and provides a potential candidate of pro-healing drug for treating diabetic wound.

Recently, it has been reported that mesenchymal stem cell (MSC)-derived humoral factors promote skin wound healing. As these humoral factors are transiently stored in cytoplasm, we collected them as part of the cell extracts from MSCs (MSC-ext). This study aimed to investigate the effects of MSC-ext on skin wound healing. We examined the effects of MSC-ext on cell proliferation and migration. Additionally, the effect of MSC-ext on skin wound healing was evaluated using a mouse skin defect model. The MSC-ext enhanced the proliferation of dermal fibroblasts, epithelial cells, and endothelial cells. It also increased the number of migrating fibroblasts and epithelial cells. The skin defects treated with MSC-ext demonstrated rapid wound closure compared to those treated with phosphate-buffered saline. The MSC-ext group exhibited a thicker dermis, larger Picrosirius red-positive areas, and a higher number of Ki67-positive cells. Our results indicate that MSC-ext promotes the proliferation and/or migration of fibroblasts, epithelial cells, and endothelial cells, and enhances skin wound healing. This suggests the therapeutic potential of MSC-ext in treating skin defects as a novel cell-free treatment modality.

Diabetic wounds are serious chronic complications of diabetes and can lead to amputation and death. Although considerable progress has been made in drugs and materials for treating it, it's still an urgent clinical problem as the materials and drugs have potential therapeutic drawbacks, such as low delivery efficiency and poor tissue permeability. To promote diabetic wound healing, a composite of thonningianin A (TA)-loaded chitosan nanoparticles (CNPS) encapsulated by a Pluronic F-127 (PF-127) hydrogel (TA-CNPS-PF) was developed in this study.

TA-CNPS was prepared by ionic gelation method and TA-CNPS was thoroughly dispersed into PF-127 hydrogel to prepare TA-CNPS-PF. The particle size, hydrogel structure, encapsulation ratio, release ratio, antimicrobial properties of TA-CNPS-PF were determined and the effect of TA-CNPS-PF on diabetic wounds was assessed. The effect of TA on macrophage polarization was also examined in vitro.

The particle size was approximately 100 nm of TA-CNPS-PF and the hydrogel had a homogeneous three-dimensional reticulation structure. The encapsulation efficiency of TA in the CNPS were 99.3% and the release ratio of TA-CNPS-PF was approximately 86% and has antimicrobial properties. TA-CNPS-PF promoted diabetic wound healing significantly. Histopathology confirmed that TA-CNPS-PF promoted complete re-epithelialization and adequate collagen deposition. TA promoted the polarization of M1 macrophages into M2 macrophages via light microscopy, immunocytometry and flow cytometry. TA-CNPS-PF also promoted an increase in the number of M2 macrophages in diabetic wounds.

TA promotes diabetic wound healing by promoting the polarization of M1 macrophages into M2 macrophages and TA-CNPS-PF has good antimicrobial activity and a good drug release ratio in this study, which provides a new direction for the treatment of diabetic wounds and is expected to be highly advantageous in clinical diabetes wound therapy.

Diabetic foot ulcer (DFU) is a chronic and non-healing wound in all age categories with a high prevalence and mortality in the world. An ideal wound dressing for DFU should possess the ability of adsorbing high contents of exudate and actively promote wound healing. Here, we introduced the calcium alginate sulfate as a new biomaterial appropriate for use in wound dressing to promote the healing of full-thickness ulcers in a diabetic mouse model. In this regard, alginate sulfate (Alg-S) solutions with different degrees of substitution (DS) of 0.2, 0.5, and 0.9 were synthesized, freeze-dried, crosslinked by calcium cations, purified by washing and refreeze-dried. Primary analyses including swelling ratio, porosity content and mechanical properties revealed that all Alg-S scaffolds possess necessities for use as a wound dressing. After confirming the cytocompatibility of both alginate and alginate sulfate-based scaffolds by MTT assay, they were used as wound dressing for healing of full-thickness ulcers in diabetic mice. The results of wound healing process confirmed that calcium alginate sulfate scaffolds can heal the wounds faster than both alginate-treated and non-treated wounds. Furthermore, the histological analyses of healed tissues reveled normal regeneration of the skin tissue layers and collagen deposition similar to the healthy tissue.

Diabetic ulcers are chronic wounds that are notoriously difficult to treat, leading to significant physical and psychological distress and increased healthcare costs. Their multifactorial aetiology necessitates long-term interdisciplinary collaboration and various complementary treatment measures. While numerous studies suggest that electrical stimulation (ES) positively impacts diabetic ulcer healing, the robustness and consistency of these findings require further evaluation to optimize clinical application. We searched databases including PubMed, the Cochrane Library, Embase, Web of Science and the China National Knowledge Infrastructure (CNKI). Only randomized clinical trials (RCTs) comparing ES treatment to placebo or conventional treatment were included. Extracted information included objective healing measures and data for assessing effect sizes. Ten RCTs involving 451 patients met inclusion criteria. ES improved ulcer healing rate compared to control or placebo (MD 20.37, 95% CI: 16.89-23.85, p <0.001) and increased the number of healed ulcers (RR 1.45, 95% CI: 1.18-1.78, p <0.001), with both results being statistically significant. The observed benefits are likely due to the positive effects of ES on the vascular and neurological functions of the lower limbs in patients with diabetic ulcers. Both low-frequency, moderate-intensity alternating current and low-intensity or high-voltage direct current have demonstrated efficacy in promoting ulcer healing. The results suggest ES may be a promising approach of managing diabetic ulcers. However, the optimal method of ES application remains undetermined; therefore, high-quality and large-scale studies are essential.

Diabetic wound exhibits the complex characteristics involving continuous oxidative stress and excessive expression of pro-inflammatory cytokines to cause a long-term inflammatory microenvironment. The repair healing of chronic diabetic wounding is tremendously hindered due to persistent inflammatory reaction. To address the aforementioned issues, here, a dual-functional hydrogel is designed, consisting of N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-tetramethylpropane-1, 3-diaminium (TSPBA) modified polyvinyl alcohol (PVA) and methacrylamide carboxymethyl chitosan (CMCSMA) can not only electrostatically adsorb proinflammatory cytokines of IL1-β and TNF-α, but can also chemically scavenge the excessive reactive oxygen species (ROS) in situ. Both in vitro and in vivo evaluations verify that the negatively charged and ROS-responsive hydrogel (NCRH) can effectively modulate the chronic inflammatory microenvironment of diabetic wounds and significantly enhance wound remodeling. More importantly, the well-designed NCRH shows a superior skin recovery in comparison with the commercial competitor product of wound dressing. Consequently, the current work highlights the need for new strategies to expedite the healing process of diabetic wounds and offers a wound dressing material with immunomodulation.

Aim: To treat diabetic wound healing with a novel Thymoquinone (TQ) loaded nanoformulation by using combination of essentials oils.Methods: TQ nanoemulsion (NE) was developed with seabuckthorn & lavender essential oils by phase inversion method and mixture design. Further, DIAGEL is obtained by incorporating NE into 1% carbopol®934. Furthermore, particle size, polydispersity index, thermodynamic stability studies, rheology, spreadability, drug content, in-vitro drug release, ex-vivo permeation, anti-oxidant assay, antimicrobial studies, angioirritance, HAT-CAM assay, in-vitro and in-vivo studies were determined.Results: NE has a particle size of 17.79 ± 0.61 nm, 0.206 ± 0.012 PDI & found to be thermodynamically stable. DIAGEL exhibited pseudoplastic behavior, sustained drug release, better permeation of TQ and a drug content of 98.54 ± 0.08%. DIAGEL stored for 6 months at room temperature and 2-8°C showed no degradation. Further, an improved angiogenesis, absence of angio-irritancy, remarkable antioxidant and antimicrobial activities against Candida albicans & S. aureus were observed. Cytotoxicity analysis revealed nearly 2.28 -folds higher IC50 value than drug solution. Furthermore, inflammatory mediators were reduced in DIAGEL treated animal groups. The histopathological studies confirmed skin healing with regeneration and granulation of tissue.Conclusion: The novel formulation has strong anti-inflammatory, angiogenesis, antioxidant and appreciable diabetic wound healing properties.

The treatment of diabetic wounds is impaired by the intricate nature of diabetes and its associated complications, necessitating novel strategies. The utilization of mesenchymal stem/stromal cells (MSCs) as a therapeutic modality for chronic and recalcitrant wounds in diabetic patients is an active area of investigation aimed at enhancing its therapeutic potential covering tissue regeneration. The threat posed to the patient and their environment by the presence of a diabetic foot ulcer (DFU) is so significant that any additional therapeutic approach that opens new pathways to halt the progression of local changes, which subsequently lead to a generalized inflammatory process, offers a chance to reduce the risk of amputation or even death. This article explores the potential of MSCs in diabetic foot ulcer treatment, examining their mechanisms of action, clinical application challenges, and future directions for research and therapy.

Diabetic wounds are usually entangled in a disorganized and self-perpetuating microenvironment and accompanied by a prolonged delay in tissue repair. Sustained and coordinated microenvironment regulation and tissue regeneration are key to the healing process of diabetic wounds, yet they continue to pose a formidable challenge. Here we report a rational double-layered dressing design based on chitosan and a degradable conjugated polymer polydiacetylene, poly(deca-4,6-diynedioic acid) (PDDA), that can meet this intricate requirement. With an alternating ene-yne backbone, PDDA degrades when reacting with various types of reactive oxygen species (ROS), and more importantly, generates proliferative succinic acid as a major degradant. Inheriting from PDDA, the developed PDDA-chitosan double layer dressing (PCD) can eliminate ROS in the microenvironment of diabetic wounds, alleviate inflammation, and downregulate gene expression of innate immune receptors. PCD degradation also triggers simultaneous release of succinic acid in a sustainable manner, enabling long-term promotion on tissue regeneration. We have validated the biocompatibility and excellent performance of PCD in expediting the wound healing on both diabetic mouse and porcine models, which underscores the significant translational potential of this microenvironment-modulating, growth-promoting wound dressing in diabetic wounds care.

Diabetic foot care has become a critical focus in global healthcare due to the rising prevalence of diabetes and its associated complications. This review aims to consolidate recent advancements and best practices in managing diabetic foot conditions, encompassing foot ulcers, neuropathy, vascular disease, and the risk of amputation. Emphasizing a multidisciplinary approach, the review advocates for collaboration among diabetologists, podiatrists, vascular surgeons, and wound care specialists to enhance patient outcomes. Key advancements highlighted include innovative wound care techniques like advanced dressings and bioengineered skin substitutes, alongside effective offloading devices to prevent pressure-related injuries. Early detection and intervention strategies for neuropathy and vascular disease are underscored, with a particular focus on vascular evaluation as a baseline investigation, including Ankle-Brachial Index (ABI) and Toe-Brachial Index (TBI) assessments by trained podiatrists and the use of arterial color Doppler/duplex scans for suspected Peripheral Artery Disease (PAD). The review also examines the impact of technological innovations such as telemedicine and wearable devices, facilitating enhanced patient monitoring and timely interventions. It stresses the importance of patient education and self-care practices in mitigating complications. Addressing global disparities, the review advocates for accessible and equitable healthcare services across diverse regions. Concluding with recommendations for future research and policy initiatives, this review serves as a vital resource for healthcare professionals, policymakers, and researchers committed to advancing diabetic foot care and improving global patient outcomes.

The treatment of diabetic foot ulcers remains a significant challenge, as their morbidity is increasing while current therapies are expensive and often ineffective. The dried mucus from the snail Achatina fulica promotes diabetic wound healing. Herein, to develop a more controllable and stable wound dressing for diabetic wound treatment, the AFG/StarPEG hydrogel mimicking snail mucus was prepared by covalently coupling of sulfated glycosaminoglycan from A. fulica (AFG) with star-shaped polyethylene glycol (StarPEG) amine. The AFG/StarPEG hydrogel reduced excessive inflammation in wound tissues by decreasing pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and increasing anti-inflammatory cytokines (IL-4 and IL-10). Moreover, it promoted the polarization of macrophages to M2 anti-inflammatory type in diabetic wound. By improving transition of diabetic chronic wound from inflammatory phase to proliferative phase, it promoted angiogenesis, collagen deposition and re-epithelialization, and thus tissue regeneration for wound healing. This work provides a convenient and effective dressing for treating chronic diabetic wound.

Diabetic foot ulcers (DFUs) are a severe complication for diabetic patients, significantly impacting patient quality of life and healthcare system efficiency. Traditional standard of care (SOC) treatments are inadequate for many patients, necessitating the use of advanced wound care products, such as human placental membranes. We studied a real-world population of large, hard-to-heal and complicated wounds, otherwise under-studied in the wound care literature. To this end, we conducted a retrospective cohort analysis to compare the effectiveness of a human placental amnion/chorion membrane product using retention-based processing (RE-AC) and SOC in managing chronic DFUs. During the study period of September 2021 through April 2024, we collected retrospective observational data from electronic health records of 21 patients treated with RE-AC at three outpatient wound care centres. Additionally, 21 control SOC patients were matched from a wound registry using Coarsened Exact Matching. Patients were categorized into two cohorts based on whether they received RE-AC or SOC. Key metrics included wound size progression and wound closure. The analysis employed Bayesian regression and Hurdle Gamma Analysis of Covariance models. Despite their rather large size (average of 13.8 cm2), our results indicated that RE-AC achieved almost a 10% higher expected wound closure rate compared to SOC at 12 weeks (8.53% [credible interval: 5.60%-10.7%]). Further, for wounds that did not close, RE-AC resulted in a 93.6% (credible interval: 147.7%-41.6) improvement in expected Percent Area Reduction over the SOC group at 12 weeks. We noted that on average, SOC wounds stalled or grew larger. In terms of a risk ratio comparing the study group with SOC, we found a 52% benefit in the RE-AC group (RR = 1.52). The findings suggest that even with larger DFUs, R-AC is superior to SOC for wound closure and expected Percent Area Reduction by 12 weeks. This benefit likely leads to reduced treatment costs, optimized resource utilization and improved outcomes in the DFU patient population; ultimately resulting in improved patient care.

Diabetic ulcers (DUs) usually suffer from severe infections, persistent inflammation, and excessive oxidative stress during the healing process, which led to the microenvironmental alternation and severely impede DU healing, resulting in a delayed wound healing. Therefore, it is particularly important to develop a medical dressing that can address these problems simultaneously. To this end, self-healing composite hydrogels were prepared in this study utilizing Bletilla striata polysaccharide (BSP) and Berberine (BER) with borax via borate ester bond. The chemical and mechanical properties of the BSP/BER hydrogels were characterized, and their wound healing performance was investigated in vivo and in vitro. The results showed that the BSP/BER hydrogel significantly accelerated wound healing in DU mice with the healing rate of 94.90 ± 1.81% on the 14th day by using BSP/BER5, and this outstanding performance was achieved by the multi-targeted biological functions of antibacterial, anti-inflammatory and antioxidant, which provided favorable microenvironment for orderly recovery of the wound. Aside from exhibiting the antibacterial rate of over 90% against both Escherichia coli and Staphylococcus aureus, the BSP/BER5 hydrogel could significantly reduce NO levels 4.544 ± 0.32 µmol/L to exert its anti-inflammatory effects. Additionally, it demonstrated a hemolysis rate and promotes cell migration capabilities at (34.92 ± 1.66%). With the above features, the developed BSP/BER hydrogel in this study could be the potential dressing for clinical treatment of DU wound.

Chronic diabetic wounds represent a significant clinical challenge because of impaired healing processes, which require innovative therapeutic strategies. This study explores the therapeutic efficacy of insulin-induced gene 1-induced bone marrow mesenchymal stem cell exosomes (Insig1-exos) in promoting wound healing in diabetic mice. We demonstrated that Insig1 enhanced the secretion of bone marrow mesenchymal stem cell-derived exosomes, which are enriched with miR-132-3p. Through a series of in vitro and in vivo experiments, these exosomes significantly promoted the proliferation, migration, and angiogenesis of dermal fibroblasts under high-glucose conditions. They also regulated key wound-healing factors, including matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-β1, and platelet endothelial cell adhesion molecule-1, thereby accelerating wound closure in diabetic mice. Histological analysis showed that Insig1-exos were more effective in promoting epithelialization, enhancing collagen deposition, and reducing inflammation. Additionally, inhibition of miR-132-3p notably diminished these therapeutic effects, underscoring its pivotal role in the wound-healing mechanism facilitated by Insig1-exos. This study elucidates the molecular mechanisms through which Insig1-exos promotes diabetic wound healing, highlighting miR-132-3p as a key mediator. These findings provide new strategies and theoretical foundations for treating diabetes-related skin injuries.

To reduce diabetes-related complications and to avoid futile procedures, foot and ankle surgeons need to understand the relative timings of catastrophic events, their incidence, and probabilities of transitions between disease states in diabetes in different patient populations. For this study, we tracked medical events (including an initial diagnosis of diabetes, ulcer, wound care, osteomyelitis, amputation, and reamputation, in order of severity) and the time between each such event in patients with diabetes, stratifying by sex, race, and ethnicity. We found that the longest average duration between the different lower extremity states was a diagnosis of diabetes to the occurrence of ulcer at 1137 days (38 months). The average durations of amputation to reamputation, osteomyelitis, wound care, and ulcer were 18, 49, 23, and 18 days, respectively. The length of each disease transition for females was greater, while those of the Hispanic population were shorter than in the total cohort. This knowledge may permit surgeons to time and tailor treatments to their patients, and help patients to address, delay, or avoid complications.

Complex microenvironments with bacterial infection, persistent inflammation, and impaired angiogenesis are the major challenges in chronic refractory diabetic ulcers. To address this challenge, a comprehensive strategy with highly effective and integrated antimicrobial, anti-inflammatory, and accelerated angiogenesis will offer a new pathway to the rapid healing of infected diabetic ulcers. Here, inspired by the tunable reactive oxygen species (ROS) regulation properties of natural peroxisomes, this work reports the design of infectious and inflammatory microenvironments self-adaptive artificial peroxisomes with synergetic Co-Ru pair centers (APCR) for programmed diabetic ulcer therapy. Benefiting from the synergistic Co and Ru atoms, the APCR can simultaneously achieve ROS production and metabolic inhibition for bacterial sterilization in the infectious microenvironment. After disinfection, the APCR can also eliminate ROS to alleviate oxidative stress in the inflammatory microenvironment and promote wound regeneration. The data demonstrate that the APCR combines highly effective antibacterial, anti-inflammatory, and provascular regeneration capabilities, making it an efficient and safe nanomedicine for treating infectious and inflammatory diabetic foot ulcers via a programmed microenvironment self-adaptive treatment pathway. This work expects that synthesizing artificial peroxisomes with microenvironments self-adaptive and bifunctional enzyme-like ROS regulation properties will provide a promising path to construct ROS catalytic materials for treating complex diabetic ulcers, trauma, or other infection-caused diseases.

To determine the profile of diabetes patients with neuropathic and neuro-ischaemic lesions who are referred to the advanced practice nurse (APN) in complex chronic wounds; to determine whether a training strategy aimed at primary care nurses and nursing homes that care for patients with diabetic foot disease influences the performance of professionals; and to assess the extent, follow-up and evaluation of diabetic foot disease in patients with neuropathic ulcers and neuro-ischaemic ulcers referred to the specialist APN before and after the training.

The characteristics of patients referred to the APN over a period of 6.5 years were analysed, as well as the numbers of amputations and deaths pre- and post-training.

of the total of 103 patients, 78 were men; across both sexes the average age was 69 years. Fifty patients had neuropathic ulcers and 53 had neuro-ischaemic ulcers, with healing rates of 59%. There were 50 amputations and 37 deaths over the study period.

Prevention of diabetic foot ulcers depends on having in place a fast, agile, practical clinical pathway between primary care and hospital, with the role of the APN, including the co-ordination of care between primary and secondary settings, being key.

Infectious diabetic wounds present a substantial challenge, characterized by inflammation, infection, and delayed wound healing, leading to elevated morbidity and mortality rates. In this work, we developed a multifunctional lipid nanoemulsion containing quercetin, chlorine e6, and rosemary oil (QCRLNEs) for dual anti-inflammatory and antibacterial photodynamic therapy (APDT) for treating infectious diabetic wounds. The QCRLNEs exhibited spherical morphology with a size of 51 nm with enhanced encapsulation efficiency, skin permeation, and localized delivery at the infected wound site. QCRLNEs with NIR irradiation have shown excellent wound closure and antimicrobial properties in vitro, mitigating the nonselective cytotoxic behavior of PDT. Also, excellent biocompatibility and anti-inflammatory and wound healing responses were observed in zebrafish models. The infected wound healing properties in S. aureus-infected diabetic rat models indicated re-epithelization and collagen deposition with no signs of inflammation. This multifaceted approach using QCRLNEs with NIR irradiation holds great promise for effectively combating oxidative stress and bacterial infections commonly associated with infected diabetic wounds, facilitating enhanced wound healing and improved clinical outcomes.

Diabetic foot ulcers often become infected, leading to treatment complications and increased risk of loss of limb. Therapeutics to manage infection and simultaneously promote healing are needed. Here we report on the development of a Janus liposozyme that treats infections and promotes wound closure and re-epithelialization. The Janus liposozyme consists of liposome-like selenoenzymes for reactive oxygen species (ROS) scavenging to restore tissue redox and immune homeostasis. The liposozymes are used to encapsulate photosensitizers for photodynamic therapy of infections. We demonstrate application in methicillin-resistant Staphylococcus aureus-infected diabetic wounds showing high ROS levels for antibacterial function from the photosensitizer and nanozyme ROS scavenging from the liposozyme to restore redox and immune homeostasis. We demonstrate that the liposozyme can directly regulate macrophage polarization and induce a pro-regenerative response. By employing single-cell RNA sequencing, T cell-deficient Rag1-/- mice and skin-infiltrated immune cell analysis, we further reveal that IL-17-producing γδ T cells are critical for mediating M1/M2 macrophage transition. Manipulating the local immune homeostasis using the liposozyme is shown to be effective for skin wound repair and tissue regeneration in mice and mini pigs.

Patients with a healed diabetic foot ulcer (DFU) have a 40% risk of ulcer recurrence within a year. New and effective measures to prevent DFU recurrence are essential. We aimed to highlight emerging trends and future research opportunities in the use of plantar pressure measurement to prevent DFU recurrence.

Our scoping review protocol was drafted using the Preferred Reporting Items for Systematic Reviews and Meta-analysis - Scoping Review protocol. Peer-reviewed, English-language papers were included that addressed both plantar pressure measurement and diabetic foot disease, either as primary studies that have advanced the field or as review papers that provide summaries and/or opinion on the field as a whole, as well as specific papers that provide guidelines for future research and advancement in the field.

A total of 24 eligible publications were identified in a literature search using PubMed. A further 36 eligible studies were included after searching the references sections of these publications, leaving a total of 60 publications included in this scoping review.

Plantar pressure measurement can and will play a major role in the prevention of DFU. There is already a strong, albeit limited, evidence base in place to prove its benefit in reducing DFU recurrence. More research is required in larger populations, using remote monitoring in real-world settings, and with improved technology.

The development of a multifunctional wound dressing that can adapt to the shape of wounds and provide controlled drug release is crucial for diabetic patients. This study developed a carboxymethyl chitosan-based hydrogel dressing with enhanced mechanical properties and tissue adherence that were achieved by incorporating pectin (PE) and polydopamine (PDA) and loading the hydrogel with recombinant human epidermal growth factor (rhEGF). This EGF@PDA-CMCS-PE hydrogel demonstrated robust tissue adhesion, enhanced mechanical properties, and superior water retention and vapor permeability. It also exhibited significant antioxidant capacity. The results showed that EGF@PDA-CMCS-PE could effectively scavenge 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate)， (1,1-diphenyl-2-picrylhydrazyl), and superoxide anions and increase superoxide dismutase and catalase levels in vivo. In vitro cytotoxicity and antibacterial assays showed good biocompatibility and antimicrobial properties. The sustained release of EGF by the hydrogel was confirmed, with a gradual release profile over 120 h. In vivo studies in diabetic mice showed that the hydrogel significantly accelerated wound healing, with a wound contraction rate of 97.84% by day 14. Histopathological analysis revealed that the hydrogel promoted fibroblast proliferation, neovascularization, and orderly connective tissue formation, leading to a more uniform and compact wound-healing process. Thus, EGF@PDA-CMCS-PE hydrogel presents a promising tool for managing chronic diabetic wounds, offering a valuable strategy for future clinical applications.

Tibial cortex transverse distraction is a surgical method for treating severe diabetic foot ulcers (DFUs), but the underlying mechanism is unclear. We show that antioxidant proteins and small extracellular vesicles (sEVs) with multiple-tissue regenerative potential are released during bone transport (BT) in humans and rats. These vesicles accumulate in diabetic wounds and are enriched with microRNAs (miRNAs) (e.g., miR-494-3p) that have high regenerative activities that improve the circulation of ischemic lower limbs while also promoting neovascularization, fibroblast migration, and nerve fiber regeneration. Deletion of miR-494-3p in rats reduces the beneficial effects of BT on diabetic wounds, while hydrogels containing miR-494-3p and reduced glutathione (GSH) effectively repair them. Importantly, the ginsenoside Rg1 can upregulate miR-494-3p, and a randomized controlled trial verifies that the regimen of oral Rg1 and GSH accelerates wound healing in refractory DFU patients. These findings identify potential functional factors for tissue regeneration and suggest a potential therapy for DFUs.