Search Results (631)

Background: Diabetic peripheral neuropathy (DPN) is a major complication of type 2 diabetes mellitus (T2D) that reduces quality of life and increases the risk of foot ulcers and amputations. Early detection is essential, and blood-based biomarkers may support improved screening and timely intervention. This study aimed to identify novel circulating biomarkers for the identification of DPN in patients with T2D. Methods: In the screening phase, plasma samples from 43 participants (10 healthy volunteers [HV], 20 T2D without complications, and 13 T2D with DPN) were analyzed using an antibody array targeting 310 proteins. Thirteen differentially expressed proteins were identified, and six hub proteins were selected through bioinformatic analysis. In the validation phase, plasma concentrations of the six proteins were measured by ELISA in 252 subjects (100 HV, 97 T2D without complications, and 55 T2D with DPN). Mucin-1 expression in sciatic nerves was further evaluated in db/db mice. Results: Of the six hub proteins (TGFB1, MUC1, PF4, IL2RA, SELL, B2M), only mucin-1 showed a significant increase in the DPN group. Plasma mucin-1 positively correlated with MNSI scores and negatively with motor and sensory nerve conduction velocities. In db/db mice, sciatic nerve mucin-1 expression was elevated, while CD31 expression was reduced. Conclusions: Plasma mucin-1 is strongly associated with DPN in both humans and animals and may serve as a promising biomarker for the screening and early identification of DPN. Full article

Background/Objectives: diabetic foot osteomyelitis (DFO) is a serious complication characterized by bone infection that can involve cortical structures, bone marrow, and surrounding soft tissues. Its prevalence ranges from 20% in moderate diabetic foot infections to over 50% in severe cases, making accurate diagnosis essential in guiding timely and effective management. in this study, we aimed to evaluate the diagnostic accuracy achieved by combining the probe-to-bone (PTB) test, plain radiography, and blood biomarkers—including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)—in the diagnosis of DFO. Methods: we conducted a diagnostic accuracy study involving 128 patients with diabetic foot ulcers and clinical suspicion of DFO. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for individual tests and for their diagnostic combinations. Results: the combination of PTB and biomarkers yielded a sensitivity of 75%, a specificity of 24%, a positive predictive value of 69%, and a negative predictive value of 29%. Similarly, the combination of PTB and plain radiography showed a sensitivity of 76%, a specificity of 23%, a positive predictive value of 62%, and a negative predictive value of 38%. When the three diagnostic modalities were analyzed together, the sensitivity reached 75%, and the specificity reached 23%. Conclusions: the combination of PTB and inflammatory biomarkers demonstrated moderate effectiveness and diagnostic performance comparable to PTB combined with radiography. These findings suggest that biomarkers may serve as a practical and accessible diagnostic adjunct in settings where imaging availability is limited or radiographic interpretation is challenging. Full article

Chronic and complex wounds, including diabetic foot ulcers, venous leg ulcers, burns and post-surgical defects, remain difficult to manage due to persistent inflammation, impaired angiogenesis, microbial colonization and insufficient extracellular matrix (ECM) remodeling. Conventional dressings provide protection, but they do not supply the necessary biochemical and structural signals for effective tissue repair. This review examines recent advances in hydroxyapatite–collagen (HAp–Col) composite dressings, which combine the architecture of collagen with the mechanical reinforcement and ionic bioactivity of hydroxyapatite. Analysis of the literature indicates that in situ and biomimetic mineralization, freeze-drying, electrospinning, hydrogel and film processing, and emerging 3D printing approaches enable precise control of pore structure, mineral dispersion, and degradation behavior. Antimicrobial functionalization remains critical: metallic ions and locally delivered antibiotics offer robust early antibacterial activity, while plant-derived essential oils (EOs) provide broad-spectrum antimicrobial, antioxidant and anti-inflammatory effects with reduced risk of resistance. Preclinical studies consistently report enhanced epithelialization, improved collagen deposition and reduced bacterial burden in HAp–Col systems; however, translation is limited by formulation variability, sterilization sensitivity and the lack of standardized clinical trials. Overall, HAp–Col composites represent a versatile framework for next-generation wound dressings that can address both regenerative and antimicrobial requirements. Full article

Background and Objectives: To evaluate and synthesize evidence on the independent clinical effectiveness, safety, and applicability of Negative Pressure Wound Therapy (NPWT) and Hyperbaric Oxygen Therapy (HBOT) in diabetic foot ulcers (DFUs), and to determine whether current evidence allows for a direct comparison between both interventions: NPWT and HBOT are widely advanced therapies for DFUs. Although both show benefits, the relative superiority of one over the other remains unclear. Systematic review of the literature conducted in accordance with PRISMA guidelines. Materials and Methods: A comprehensive literature search was performed using two electronic databases. The review included randomized controlled trials, systematic reviews, meta-analyses, and non-randomized studies. Methodological quality and risk of bias were assessed using validated tools: RoB 2.0 for randomized trials, AMSTAR-2 for systematic reviews, and ROBINS-I for non-randomized studies. Results: A total of 22 studies were included. NPT was shown to be effective in accelerating wound healing, though results varied depending on the type of intervention and clinical context. HBOT demonstrated beneficial effects on angiogenesis and significantly reduced the rate of major amputations. Both therapies presented significant advantages in the management of diabetic foot ulcers. Conclusions: Negative pressure therapy and hyperbaric oxygen therapy are both effective treatments for diabetic foot ulcer healing. However, treatment selection should be individualized based on patient-specific clinical factors, ulcer severity, and available healthcare resources. Integrating these advanced therapies within a multidisciplinary care approach may optimize outcomes and reduce the risk of complications. Future research should include standardized, head-to-head RCTs. Full article

Diabetic foot ulcers (DFUs) represent 6.3% of the various complications of type 2 diabetes mellitus, with a risk of development of up to 34%. Several factors contribute to the formation of ulcers, which are very difficult to treat as they hinder efficient wound healing. Patients experience persistent pain, which leads to the consumption of various medications (polypharmacy) due to the lesions not resolving. Conversely, this can increase the risk of various factors, including a chronic inflammatory state, which hinders the body’s own regenerative processes. Until now, treatment options have been limited to washing the wound and stimulating new tissue growth, but this is a painful and unsuccessful process. One of the treatment options is therefore cell therapy with mesenchymal stem cells, which have immunomodulatory characteristics and allow tissue regeneration, although the effect directly in pain is not totally clear. We have previously reported in our working group that patients with ulcers treated with mesenchymal stem cells (MSCs) have been able to integrate into their daily lives, although the pain related to the inflammatory state and polypharmacy has not been studied. Objective: This study investigates how the local administration of MSCs improves the condition of an ulcer by inducing tissue regeneration. It also shows how the concentration of systemic inflammatory biomarkers is modified in direct correlation with pain and the consumption of medications over time. Methods: Local administration of MSCs at 7 and 14 days, measuring pro- and anti-inflammatory cytokines relative to the healthy control group, evaluating wound healing, and monitoring the medications taken by the patient in conjunction with pain perception. Results: Cell administration showed that inflammatory molecules were reduced and anti-inflammatory molecules increased. This is reflected in the consumption of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in relation to wound improvement, with a decrease in pain medication consumption of less than 50%. We provide evidence that locally administered mesenchymal stem cells influence systemic inflammatory processes necessary for tissue recovery, impacting patients’ polypharmacy consumption due to reduced perceived pain. Conclusions: This report establishes a direct link between mesenchymal stem cells and pain relief in type 2 diabetes ulcers, potentially paving the way for new pain therapies. Full article

Diabetic foot ulcers (DFUs) are a major complication of diabetes, affecting 19–34% of diabetic patients in their lifetime. Decreased angiogenesis, altered extracellular matrix (ECM) remodeling, and chronic inflammation underlie the pathophysiology of nonhealing DFU. Further, MAPK13, which regulates matrix remodeling and promotes inflammation, CXCR2, an IL-8 receptor that drives inflammation, and thrombospondin-1 (TSP-1), which inhibits angiogenesis, play a role in wound healing, but the effect of hyperglycemia on the expression of these mediators during wound healing is not well understood. This study aims to investigate the effects of hyperglycemia on the expression of MAPK13, CXCR2, and TSP-1. Type 2 diabetes was induced in high-fat-fed Sprague Dawley rats using low-dose streptozotocin. Cutaneous wounds were created on the dorsum of control and diabetic rats. Tissue samples were collected during and after wound healing (n = 7 per group; total = 28) and used in this study to investigate the gene and protein expression of MAPK13, CXCR2, and TSP-1 in normal and healed skin using RT-qPCR and immunostaining. The results suggest that hyperglycemia increases the expression of TSP1 and CXCR2, and the effects on MAPK13 are context-dependent. Our results provide potential insights into impaired healing in diabetic wounds and highlight therapeutic targets for chronic DFUs by targeting angiogenesis, ECM remodeling, and chronic inflammation. Full article

Background: Wounds with an avascular component represent a significant challenge in medical care due to impaired blood flow. Synthetic matrices, such as poly-lactic acid (PLA), have demonstrated promising results in promoting wound healing in complex wounds, including those with restricted blood supply, such as diabetic foot and venous leg ulcers. Objective: This case series presents the outcomes of five patients with wounds containing exposure of avascular components, of various etiologies successfully treated with PLA matrices. Case description: Five patients presented complex wounds involving exposure of bone, tendon, fascia, or osteosynthetic material. Wound bed preparation included debridement followed by PLA application covered with additional layers (non-adherent dressing, absorbent dressing, and compression bandage) as needed. Weekly assessments were conducted until full wound closure was achieved. Results: All cases showed successful outcomes, with PLA promoting granulation tissue formation and re-epithelialization, contributing to wound closure. One patient required skin grafts for complete healing. No local infections were reported before or after PLA application. Conclusions: PLA matrices are a practical and effective option for managing complex wounds, promoting tissue regeneration and optimizing wound bed quality for skin grafts or flaps. While these findings are promising, further studies are needed to confirm the broader applicability and efficacy of PLA in the management of wounds containing exposure of avascular structures. Full article

Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction, posing a substantial global health challenge. This review systematically summarizes the therapeutic potential of berberine, a natural isoquinoline alkaloid, in the management of T2DM. Berberine’s pharmacological activities are discussed from multiple perspectives, including enhancing insulin sensitivity and regulating glucose metabolism—encompassing glycogen synthesis, gluconeogenesis, and glucose transport. The review also highlights berberine’s anti-inflammatory, antioxidant, and epigenetic enzyme-targeting actions and its involvement in key T2DM-related signaling pathways such as AKT, AMPK, and GLUTs. These findings collectively elucidate the multi-targeted and multi-pathway molecular mechanisms underlying berberine’s efficacy against T2DM. Additionally, the review covers the pharmacological activities and molecular mechanisms of berberine in treating T2DM complications—including diabetic nephropathy, retinopathy, cardiomyopathy, neuropathy, and diabetic foot ulcers—as well as its clinical and preclinical applications and the synergistic benefits of combination therapy with agents such as metformin, ginsenoside Rb1, and probiotics. By systematically reviewing the literature retrieved from PubMed and Web of Science up to 2025, this article provides a comprehensive summary of current research, offering a theoretical foundation for the clinical use of berberine in T2DM therapy. Full article

Diabetic foot ulcers (DFUs) are a leading cause of morbidity worldwide along with the risk of other chronic health issues. Hyperglycemia has been shown to alter immune regulation at the wound site and potentially contributes to non-healing DFUs. However, the effects of hyperglycemia on the expression of mediators of inflammation and angiogenesis (CD36), immune regulation (TLR-7 and CD69), and inflammation/tissue repair (CD274) regarding wound healing are unknown. This study aims to investigate the effects of hyperglycemia on the gene and protein expression of CD36, CD69, CD274, and TLR-7 during wound healing using a rat model of induced diabetes. The expression of these mediators was examined using cutaneous tissues from rat models of diabetes with cutaneous wounds. Skin samples (n = 7 each, control and healed) from the control and diabetic rats were analyzed using hematoxylin and eosin as well as trichrome staining, immunohistochemistry, and PCR. In vitro studies were conducted using rat fibroblasts. Hyperglycemia significantly increases the expression of CD36, CD69, and CD274 and increases TLR-7 expression but not significantly in diabetic tissues compared to control tissues. In vitro studies corroborate the findings in tissues. The modulation of these mediators by hyperglycemia suggests their probable role in delayed wound healing, and these mediators may be potential therapeutic targets to promote wound healing in DFUs. Full article

Objective: To establish a reliable machine-learning-based model for predicting the risk of lower limb amputation in patients with diabetic foot ulcers and to provide quantitative evidence for clinical decision-making and individualized prevention strategies. Methods: This retrospective study analyzed data from 149 hospitalized diabetic foot ulcer patients treated at Beijing Shijitan Hospital between January 2019 and December 2022. Patients were divided into amputation and non-amputation groups according to clinical outcomes. Candidate predictors—including infection biomarkers, vascular parameters, and nutritional indices—were first screened using the least absolute shrinkage and selection operator algorithm. Subsequently, a support vector machine model was trained and internally validated via five-fold cross-validation to estimate amputation risk. Model performance was evaluated by discrimination, calibration, and clinical utility analysis. Results: Among all enrolled variables, C-reactive protein and Wagner grade were identified as independent predictors of amputation (p < 0.05). The optimized support vector machine model achieved excellent discrimination, with an area under the Receiver Operating Characteristic curve of 0.89, and demonstrated a moderate level of calibration (Hosmer–Lemeshow χ² = 19.614, p = 0.012). Decision curve analysis showed a net clinical benefit of 0.351 when the threshold probability was set at 0.30. The model correctly classified 82.4% of cases in internal validation, confirming its predictive robustness and potential for clinical application. Conclusions: C-reactive protein and Wagner grade are key determinants of amputation risk in diabetic foot ulcer patients. The support vector machine-based prediction model exhibits strong accuracy, clinical interpretability, and personalized interventions. Full article

Background/Objectives: Diabetic foot ulcers (DFUs) are one of the most debilitating complications of diabetes mellitus, characterized by impaired wound healing, chronic inflammation, and neuropathy. Peripheral nerve degeneration plays a critical role in delayed healing, but the molecular mediators linking hyperglycemia, neurodegeneration, and impaired DFU repair remain incompletely understood. This study aims to characterize the expression of activin A, which is a key regulator of fibroblast activity and neuronal growth, tumor necrosis factor receptor superfamily member 10B (TNFRSF10B), which mediates inflammatory and apoptotic signaling, and synaptophysin, which serves as a marker of axonal sprouting and synaptic remodeling in diabetic tissues. Methods: Skin tissues during wounding and after healing from control and diabetic Sprague–Dawley rats were analyzed using histological staining, immunohistochemistry, and quantitative real-time polymerase chain reactions. Additionally, rat fibroblasts were treated with hyperglycemic medium to evaluate gene and protein expression in vitro. Results: Histological analyses revealed impaired healing in diabetic wounds with reduced collagen deposition, loss of adnexal structures, and disorganized tissue architecture. Gene and protein expression of activin A, TNFRSF10B, and synaptophysin were significantly decreased in diabetic healed tissues compared to controls. In vitro, hyperglycemia induced transient upregulation of activin A and TNFRSF10B at 24 h, followed by a decline at 48 and 72 h. Conclusions: These findings indicate that hyperglycemia disrupts key mediators of axonal regeneration in DFUs, potentially contributing to impaired neuronal regeneration and delayed healing. Targeting these molecular pathways may offer therapeutic opportunities to enhance wound repair in DFUs. Full article

Chronic infections pose significant clinical challenges due to their persistent nature, heightened resistance to conventional therapies, and association with biofilm formation. Neutrophil extracellular traps (NETs), released through a unique form of cell death known as NETosis, serve as an innate immune defense mechanism by trapping and neutralizing pathogens. However, accumulating evidence reveals a complex and paradoxical relationship between NETs and microbial biofilms. While NETs can immobilize and kill planktonic microbes, the extracellular DNA and associated proteins often contribute to biofilm stability, immune evasion, and chronic infection persistence. This review explores the bidirectional interactions between NETosis and biofilm formation, with a focus on their synergistic roles in the pathogenesis of chronic infections such as cystic fibrosis lung disease, diabetic foot ulcers, periodontitis, and implant-associated infections. We outline the molecular mechanisms governing NETosis, the structural and functional dynamics of biofilms, and how these processes intersect to form recalcitrant infection niches. Emerging therapeutic strategies aimed at disrupting this pathogenic interplay including DNase-based treatments, PAD4 inhibitors, and combination therapies are critically evaluated. By illuminating the pathogenic synergy between NETs and biofilms, this review underscores the need for integrated immunomodulatory and anti-biofilm interventions to effectively manage chronic infectious diseases and improve patient outcomes. Full article

Background: Chronic cutaneous wounds such as diabetic foot ulcers, venous leg ulcers, pressure injuries, and burns remain a global clinical burden. These wounds are often arrested in inflammatory or ischemic stages due to impaired angiogenesis and growth factor deficiencies. Biologic therapies, such as platelet-rich plasma (PRP) and recombinant growth factors, aim to restore these deficits and accelerate repair. Methods: A narrative review of PubMed and Google Scholar (2015–2025) identified 64 English-language studies, including randomized controlled trials, meta-analyses, and translational investigations evaluating PRP and recombinant growth factors in wound healing. Results: Randomized trials and meta-analyses show that adjunctive autologous PRP increases complete wound closure versus standard care in chronic ulcers, including diabetic foot and venous leg ulcers (odds ratios ≈ 2–8), and improves healing rates in pressure injuries (odds ratio ≈ 3.4), without increasing adverse events. In diabetic foot ulcers, PDGF-BB and EGF, together with PRP, consistently improve complete healing and reduce ulcer area. In burns, topical EGF and bFGF shorten healing time by ~3 days in superficial partial-thickness wounds and by >5 days in deeper burns, with generally improved scar outcomes. Conclusions: PRP offers broad, autologous biologic activation, while recombinant growth factors deliver high-potency, targeted precision. Together, they represent complementary regenerative strategies that can shorten healing times and improve outcomes in chronic wounds. Standardized multicenter trials quantifying cytokine composition, cost-effectiveness, and long-term limb-salvage benefit are warranted to guide their integration into routine clinical practice. Full article

Background/Objectives: The aim of this study was to identify systemic, metabolic, and host-related prognostic factors for long-term outcomes in patients with a diabetic foot ulcer (DFU). Methods: One hundred patients were selected from a high-risk cohort of 426 individuals with a DFU (January 2021–January 2023) based on predefined inclusion and exclusion criteria. Clinical, laboratory, and imaging data were collected. Outcomes were categorized as favorable (healing) or unfavorable (non-healing, re-ulceration, amputation, or death). Prognostic factors were analyzed using random forest and categorical boosting models, with SHAP values to determine the importance of individual predictors. Results: The median age of participants was 65 years (interquartile range [IQR], 57–69.25), and the median duration of diabetes was 18 years (IQR, 12–26). Over a mean 2.1-year follow-up, unfavorable outcomes occurred in 53% of the whole cohort and in 36% of survivors. The strongest predictors of poor prognosis were prior amputation, elevated inflammatory markers, reduced eGFR, and dyslipidemia. Triglycerides showed a U-shaped association with outcomes. A lower BMI and shorter diabetes duration paradoxically were also linked to poorer prognosis. Glycemic control, comorbidities, and local foot characteristics had limited predictive value. Conclusions: Long-term DFU prognosis is driven mainly by systemic and host-related factors rather than by ulcer characteristics alone. Inflammation, renal dysfunction, dyslipidemia—particularly triglycerides—and prior amputation were the strongest predictors of unfavorable outcomes. Full article

The purpose of this analysis is to report on the clinical efficacy of Continuous Diffusion of Oxygen (CDO) therapy in real-world clinical practice and compare those results to data published in controlled clinical studies. For the real-world clinical results, a Prospective Patients Database (PPD) of 764 patients treated using CDO therapy in a broad range of clinical practices across a wide range of wound types and wound locations was analyzed. The objectives included analyzing the clinical efficacy of CDO therapy across multiple wound types and anatomical locations, testing the data for robustness, and comparing the efficacy to results from controlled clinical studies for CDO and NPWT. The PPD data is also analyzed for efficacy among the sexes and by age for older patients in the Medicare population. The robustness of the PPD data is tested using various non- and semi-parametric statistical tools, including the Kaplan–Meier and Cox proportional hazard (PH) models, among others. The results show that CDO therapy is highly efficacious with an average healing success rate of 76.3% in real-world application, ranging from 71.2% to 84.1% for different wound types. The Medicare age population had an average age of 78 years old and similar healing rates to the overall population, with slightly better results for pressure ulcers in the older patient population. The PPD data proved to be extremely robust in every test method, demonstrating substantially equivalent efficacy in various wound types and locations, as well as between men and women. The PPD results for CDO compared favorably to clinical trial results for CDO and NPWT. Both clinical trial and PPD data for CDO exhibited better healing rates when compared to NPWT. Kaplan–Meier analysis shows that CDO use in clinical practice has 79.2% full closure in 112 days, as compared to NPWT, which has 43.2% full closure in the same timeframe for similar wound sizes and severity. These results demonstrate not only that CDO is highly efficacious in clinical practice, but that the efficacy is also similar across all wound types and locations in the body. CDO also compares very favorably to NPWT. Full article