Diabetic foot ulcers (DFUs) are a serious complication of diabetes mellitus. Statins are widely used for treatment of dyslipidaemia and prevention of cardiovascular events. They also exert multiple pleiotropic effects, including improvement of endothelial function, and promotion of angiogenesis and tissue repair. Accumulating evidence suggests that these properties may be beneficial in diabetic wound healing. The aim of this comprehensive review was to summarise preclinical and clinical data regarding the potential role of statins in DFUs management. Experimental studies consistently demonstrated that statins promote wound healing through several mechanisms, including increased nitric oxide bioavailability, vascular endothelial growth factor (VEGF)-mediated angiogenesis, improved endothelial function, and increased collagen synthesis and deposition. Emerging drug-delivery strategies, including topical formulations and tissue-engineered scaffolds, further improved therapeutic efficacy. Clinical evidence remains limited but encouraging. Observational studies have reported inconsistent findings, whereas randomised controlled trials suggest that statins may reduce ulcer recurrence and accelerate wound healing without significant safety concerns. Overall, the evidence supports a strong biological rationale for the use of statins as adjunctive therapy in DFUs. However, further research is required to establish their clinical efficacy, dosage, route of administration and treatment duration.
ObjectiveTo evaluate the clinical severity and microbiological characteristics of participants with type 2 diabetes and foot ulcers (DFUs) screened for eligibility into a bacteriophage therapy pilot study.Research Design And MethodsAdults aged (≥18 years) with type 2 diabetes mellitus (T2DM) and active DFUs presenting to a tertiary care centre were screened using predefined eligibility criteria. Ulcers were graded according to the University of Texas Diabetic Foot Classification System. Microbiological analysis included standard culture techniques and biochemical tests for identification of microorganism. Descriptive statistics were used to summarize ulcer severity, microbial patterns, and eligibility outcomes.ResultsA total of 595 individuals were screened. Grade 3 ulcers accounted for 51.1% of cases, followed by Grade 2 (29.1%) and Grade 1 (19.8%). Monomicrobial infections were identified in 63.7% of individuals, polymicrobial infections in 17.6%, and no growth in 18.7%. Gram-negative organisms predominated, including Pseudomonas spp. (n = 74), Escherichia spp. (n = 60), Klebsiella spp. (n = 50), Proteus spp. (n = 43), and Acinetobacter spp. (n = 25). Among Gram-positive organisms, Staphylococcus spp. (n = 81) and Enterococcus spp. (n = 43) were common.ConclusionsThe screened population demonstrated a high burden of advanced Grade 3B DFUs, predominantly associated with Gram-negative pathogens amenable to bacteriophage targeting. But this pilot study intentionally focused on Grade 1B and Grade 2B ulcers to assess the feasibility and safety of bacteriophage therapy in predefined, less severe DFUs. This pre-screening process supported the feasibility and enrollment of eligible participants for the subsequent bacteriophage therapy pilot study.
AimsCharcot neuro-osteoarthropathy (CN) is a rare but severe diabetes-related complication characterized by neuropathy, inflammation, and progressive bone and joint destruction. Advanced glycation end products (AGEs) may contribute to diabetes complications through protein glycation and activation of AGE-receptor for AGE (RAGE)-associated inflammatory and oxidative-stress pathways. This cross-sectional case-control study compared AGEs, soluble RAGE (sRAGE), and oxidative-stress markers among individuals with diabetes and CN (DM/CN), individuals with diabetes without CN (DM/noCN), and healthy controls.Research Design and MethodsThis was a case-control study on 15 people with active or chronic DM/CN, 33 individuals with DM/noCN and 26 age-matched healthy controls. Subjects underwent thorough clinical evaluation; AGEs were measured in lens via autofluorescence and in serum samples. Serum levels of sRAGE and reactive oxygen markers were also determined.ResultsParticipants with DM/CN had higher lens and serum AGE levels and oxidative stress than those with DM/noCN. Both diabetes groups had higher AGEs, sRAGE, and oxidative-stress levels than healthy controls. AGEs, sRAGE, and oxidative stress were associated with peripheral neuropathy, and CN was independently associated with higher circulating AGE concentrations after adjustment for HbA1c and BMI.ConclusionsIndividuals with diabetes and CN exhibit increased AGE accumulation and oxidative stress compared with individuals with diabetes without CN. These findings support a potential role for AGE-associated inflammatory and oxidative-stress pathways in the pathophysiology of CN. Larger prospective studies are needed to determine the clinical and prognostic value of AGEs, sRAGE, and oxidative-stress markers in CN.
Diabetic foot ulcers frequently lead to amputation, and early risk identification remains challenging. Although the neutrophil-to-lymphocyte ratio (NLR) may predict amputation risk, supporting evidence remains limited. This study evaluated the association between NLR and amputation risk in patients with diabetic foot (DF). We systematically searched PubMed, Embase, Scopus, Cochrane Library, and Web of Science up to May 31, 2026. Studies reporting NLR value in DF patients with and without amputation were included. The primary outcome was the pooled mean difference (MD) in NLR between groups. Additionally, We performed a diagnostic accuracy analysis extracting sensitivity and specificity. Odds ratios (ORs) for amputation based on NLR were summarized descriptively. Study quality was assessed with the Newcastle-Ottawa Scale (NOS). Fifteen studies comprising 2757 patients were included. The amputation group had significantly higher NLR than the non-amputation group (pooled MD 3.66, 95% CI 2.60-4.71; I2 = 81%). For major versus minor amputation, the pooled MD was 4.00 (95% CI 1.81-6.19; I2 = 96%). Diagnostic analysis showed moderate discriminatory ability (area under the curve [AUC] 0.798), with a pooled sensitivity of 0.71 (95% CI 0.66-0.75), specificity of 0.71 (95% CI 0.66-0.75), and a diagnostic odds ratio of 6.85 (95% CI 3.54-13.27). Furthermore, studies reporting ORs indicated a positive association between elevated NLR and amputation risk. In conclusion, elevated NLR is significantly associated with amputation risk in DF patients, including major versus minor amputation. Diagnostic analysis suggests moderate discriminatory ability. However, substantial heterogeneity was observed across studies, which warrants caution in interpreting the pooled estimates. Despite this limitation, NLR remains a valuable, cost-effective biomarker for identifying high-risk patients, particularly in resource-limited settings.
Plantar ulcers associated with Charcot neuroarthropathy (CNO) are difficult to treat because of persistent abnormal pressure distribution and foot instability. Although traditional non-removable total contact casting (TCC) remains the standard offloading method, it limits direct wound inspection and routine dressing care. This prospective study evaluated the effectiveness and safety of a modified windowed angled TCC technique for resistant weight-bearing plantar ulcers in patients with Charcot deformities. This prospective single-center study was conducted between May 2024 and March 2026. Forty-eight diabetic patients with midfoot or hindfoot Charcot neuroarthropathy and chronic weight-bearing plantar ulcers resistant to previous conservative offloading methods were included. Adequate distal perfusion was confirmed in all patients using vascular assessment. Windowed angled total contact casts were customized by adjusting the ankle position according to ulcer location to reduce plantar pressure while maintaining direct wound access for regular inspection and dressing changes. The primary outcome was complete ulcer healing. Secondary outcomes included secondary infection and cast-related pressure complications. A total of 48 patients (23 males and 25 females) were evaluated; 29 patients (60.4%) had clinically infected ulcers. Complete ulcer healing was achieved in 44 patients (91.7%). Among healed ulcers, 9 patients (20.4%) healed within 12 weeks, 29 patients (65.9%) healed within 12-24 weeks, and 6 patients (13.6%) required more than 24 weeks. Four patients (8.3%) remained unhealed because of extensive tissue loss and severe deformity. Secondary infection during treatment occurred in 4 patients (8.3%), while minor cast-related pressure sores developed in 2 patients (4.1%). Windowed angled total contact casting was an effective and safe offloading technique for resistant plantar ulcers in patients with Charcot neuroarthropathy. The technique combines rigid immobilization with direct wound access, allowing effective pressure redistribution and regular wound care during treatment.
Backgrounddiabetic foot ulcers (DFUs) carry 5-year mortality rates of 50%-70% and recurrence rates of 65% at three to five years. Standard-of-care protocols fail to resolve wound chronicity in a substantial proportion of patients, reflecting incomplete understanding of the cellular mechanisms sustaining non-healing. This narrative review examines trace element dyshomeostasis as a mechanistically distinct driver of ferroptotic cell death across wound-bed cell populations and evaluates targeted therapeutic strategies within this framework.MethodsLiterature was identified through narrative searches of PubMed and Web of Science; emphasis was placed on DFU-relevant experimental models and clinical populations.ResultsLabile iron pool expansion, arising from hemolysis-derived Fe2+ release, vasa nervorum compromise, ferritinophagy dysregulation, and SASP-mediated ferroportin suppression, sustains iron-catalyzed lipid peroxidation across Schwann cells, endothelial cells, fibroblasts, and macrophages. Three upstream metabolic axes, comprising AGEs/RAGE-mediated SLC7A11 suppression, eNOS uncoupling with BH4 depletion, and macrophage iron overload-driven polarization arrest, collectively lower the ferroptotic threshold at the wound margin. AGE-induced ECM stiffening further impairs fibroblast antioxidant capacity via mechanotransduction, while impaired NCOA4-dependent ferritinophagy renders senescent fibroblasts ferroptosis-resistant, sustaining SASP-driven iron retention in neighboring cells. Localized deferoxamine delivery stabilizes HIF-1α and restores angiogenic signaling in preclinical models; selenium supplementation restores GPX4-mediated lipid hydroperoxide clearance. Stimuli-responsive biomaterials coordinating DFO and antioxidant release in response to pathological ROS, MMP, and pH signatures represent a tractable delivery framework.ConclusionIron dyshomeostasis and ferroptosis constitute a therapeutically actionable axis in DFU pathology unaddressed by current standard of care. Large animal model validation and pharmacokinetic profiling in the DFU wound environment remain necessary before clinical translation.
This study aimed to evaluate the relationship between fear of falling, foot care behaviors, and comfort levels in patients with diabetic foot. This descriptive and cross sectional study included 285 patients diagnosed with diabetic foot who attended the wound care clinic of a hospital. Data were collected using a patient assessment form, the Tinetti Falls Efficacy Scale, the Foot Care Behavior Scale, and the General Comfort Scale-Short Form (GCS-SF). The mean total score of the participants on the Tinetti Falling Efficacy Scale was 59.20 ± 17.16. A weak positive correlation was found between the total score of the Tinetti Falling Efficacy Scale and the total score of the Foot Care Behavior Scale (r = 0.278, p < .01). A weak positive correlation was found between the total score of the Tinetti Falling Efficacy Scale and the GCS-SF (r = 0.231, p < .01). Multiple linear regression analysis showed that Wagner classification was a significant predictor of Tinetti Falling Efficacy Scale scores (B = -7.910, β = -0.599, p < .001), whereas foot care behaviors and GCS-SF scores were not significant predictors. Fear of falling was correlated with foot care behaviors and comfort levels.
Diabetic foot ulcers (DFU), a prevalent chronic wound, pose severe threats to patients’ quality of life. Recently hydrogel dressings have emerged as a promising therapeutic option for DFU. This study aimed to gain the current status, hotspots and research orientation of the field via analyzing the characteristics of both literature and patents on hydrogel dressings for DFU therapy. The literature and patents were retrieved and screened from the Web of Science Core Collection database and the IncoPat global patent database, respectively. The bibliometric analysis was conducted by CiteSpace 6.1.R6. We found that both articles and patents related to the field surged since 2019 in parallel. Research on this topic has involved 43 countries worldwide; two large-scale collaborative clusters were respectively led by China and Spain; Wenzhou Medical University and D.G. Armstrong are the core institution and researcher. Through analyzing literature, angiogenesis, drug delivery and inflammation are the core focus, while conductive hydrogels and therapy strategy have become emerging research hotspots. Given the patents, the focus of hydrogels for DFU are concentrated on clinical application scenarios, hydrogel preparation and drug loading. In conclusion, both literature publication and patent application have garnered increasing academic attention and recognition. Effective and productive hydrogel represent a promising therapeutic option for DFU patients.
Purpose This study aims to evaluate the antioxidant, antibacterial, and wound-healing properties of powders from Cytisus triflorus and Teucrium polium , plants endemic to Algeria harvested during two phenological stages and for enhancing wound care using a rat wound model. Methods Phytochemical characterization of powders has involved: total phenol, flavonoids and condensed tannins content, as well as the carbohydrates composition. Such investigation was supported by their efficiency as antibacterial and antioxidant determined by different test systems, namely DPPH radicals scavenging activity, reducing power and β-carotene bleaching assay. In this regard, a rat excision wound model was used to assess wound healing. Wound contraction, hydroxyproline contents and histological evaluation were performed. Results Powders from studied plants differed predominantly in their total phenol, flavonoids and condensed tannins content as well as the carbohydrates composition between phenological stages. Indeed, the powders from both plants harvested at the flowering stage showed a potential antioxidant activity and exhibited significant antibacterial activity against Gram positive bacteria. After twelve days of treatment in excision wound model, wound contractions for Cfl’Ont and Tfl’Ont ointments mention a value of 100% which it showed highly significant temporal reduction in those wounds area ( P < .01) followed by Cfr’Ont and Tfr’Ont ointments with 98.11%, 96.88%, decreased epithelialization time, arranged derma and increased hydroxyproline content over the reference groups during the trial. Conclusion Our findings have proved, for the first time, scientific evidence of the efficiency of Algerian plants namely Cytisus triflorus L'Her and Teucrium polium to possess a remarkable wound healing activities supporting the folkloric assertion.
AimTo compare topical rifamycin versus a chlorhexidine-containing wound dressing for wound healing and microbial load in infected and non-infected wound models.MethodsThirty rats were studied in two stages across five groups (n = 6). Full-thickness 1 × 2 cm interscapular wounds were created. Group 1 received saline irrigation (control), Group 2 topical rifamycin, Group 3 chlorhexidine-containing dressing (CHD), Group 4 infection with Staphylococcus aureus ATCC 25923 followed by rifamycin, and Group 5 the same infection followed by CHD. Animals were housed individually. On day 7, rats were sacrificed and wounds excised; specimens were divided equally for microbiology and histology.ResultsOn day-7 histology, the control group had the lowest wound healing score (7.66 ± 0.82). The highest score occurred in the CHD group (11.33 ± 1.75), followed by the rifamycin group (10.5 ± 0.55). No significant differences were found between non-infected groups (p = 0.292) or infected groups (p = 0.360). In infected groups, the CHD group showed lower total bacterial colony counts and fewer colonies per milligram of tissue, but differences were not significant (p = 0.091, p = 0.200).ConclusionCHD tended to outperform rifamycin in wound healing and limiting bacterial growth, but no significant difference was detected. This study informs clinical use of both products.
Peripheral arterial disease (PAD) is one of the most common underlying causes of major lower extremity amputations (LEAs). Often revascularization is not adequate to save the leg. Tibial Transverse Transport (TTT) represents a revolutionary approach to increase angiogenesis in people with critical limb threatening ischemia (CLTI). A systematic review and meta-analysis was conducted across six databases. Inclusion criteria required studies to evaluate TTT combined with revascularization versus revascularization or TTT alone as a monotherapy. Outcomes analyzed included tarsal-metatarsal amputation (TMA), wound healing, and change in visual analogue scale (VAS) for pain. A total of five studies were identified across four databases that met inclusion criteria. TTT + Revascularization was shown to have a protective effect in reducing follow up TMA, O.R = 0.44 [0.23, 0.81], p = 0.009. TTT + Revascularization was also found to have an association with wound healing, OR = 3.25 [1.84,5.73], p = 0.0001. Four studies observed the change in Visual Analogue Scale (VAS), and the cumulative effect showed no association between either TTT + Revascularization or monotherapy with change in VAS pain pre and post procedure, standard mean difference = -0.05 [-0.16, 0.05], p = 0.33. TTT in combination with peripheral endovascular revascularization offers a promising addition for patients with CLTI with lower incidence of TMA increase rates of wound healing. However, considering the limited studies available and overall small sample size, further trials are necessary to understand the relationship between this novel therapy and CLTI management.
ImportanceTissue healing is a complex physiological process that includes the phases of inflammation, proliferation, and remodeling. Interruption in these processes may cause delays in the healing process and lead to abnormal scar formation, which may affect the functional and aesthetic outcomes. Microcurrent electrical stimulation, which uses electrical currents in the range of microamperes, similar to the endogenous bioelectric currents, has been developed as a therapeutic technique to modulate tissue healing and abnormal scar formation.ObjectiveTo assess the clinical effectiveness of microcurrent electrical stimulation in the promotion of tissue healing and the modification of scar formation.Evidence ReviewA systematic review of clinical studies was performed using the PRISMA 2020 approach and registered in PROSPERO (CRD420261285174). An electronic search of PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library was performed, covering all available literature up to 2024. Clinical studies involving human subjects with wounds, tissue injuries, or scar formations treated with microcurrent electrical stimulation (MES) were included. The study types included randomized controlled trials, controlled clinical trials, and prospective or retrospective clinical studies. The main parameters evaluated were the wound healing rate, time for wound healing, and scar thickness, pliability, and appearance. The risk of bias in the included studies was evaluated using the Cochrane Risk of Bias 2 tool.ResultsEleven studies (2012-2024) suggest MES may enhance wound healing and improve scar outcomes; however, results are inconsistent due to variability in protocols, populations, and assessment methods.Conclusionsand Relevance: Microcurrent electrical stimulation (MES) may improve wound healing and scar outcomes, but current evidence is limited by study variability and small sample sizes. It should be considered a complementary therapy, with further robust trials needed to confirm efficacy and optimize treatment protocols.
BackgroundCharcot neuro-osteoarthropathy (CNO) is a limb-threatening diabetic foot complication involving neuropathy, repetitive trauma, inflammation, and bone remodeling. Obesity is common in CNO, but observational interpretation is limited by confounding and reverse causation.MethodsWe performed two-sample MR using GWAS summary statistics. The primary outcome was FinnGen R12 Charcot foot. BMI was prespecified as primary; glycemic traits, lipids, metabolic traits, and heel bone mineral density (BMD), a systemic proxy for skeletal strength, were secondary or comparator exposures. Instruments were genome-wide significant and European LD-clumped.ResultsPer standardized BMI increment, higher BMI was strongly associated with Charcot foot (odds ratio [OR], 3.36; 95% CI, 2.30-4.92; P = 4.01 × 10-10); 1 standardized BMI unit is approximately 4.7 to 4.8 kg/m2 in large European cohorts. BMI was nominally associated with diabetic neuropathy (OR, 1.21; 95% CI, 1.04-1.42; P = 0.016). Fasting glucose was suggestive (OR, 2.35; 95% CI, 1.14-4.81; P = 0.020). Higher heel BMD was associated with lower Charcot foot risk (OR, 0.75; 95% CI, 0.59-0.96; P = 0.021).ConclusionsGenetically proxied higher BMI was strongly associated with Charcot foot risk; fasting glucose and heel BMD-proxied skeletal findings were suggestive. These findings support considering adiposity in long-term risk recognition alongside neuropathy surveillance, foot protection, and offloading.
BackgroundClinical guidelines conventionally define nutritional adequacy using a 35 g/L serum albumin threshold. However, its biological sufficiency for driving diabetic foot ulcer (DFU) regeneration remains unvalidated. This investigation utilized a structural modeling framework to interrogate the non-linear relationship between albumin and DFU repair and to identify the precise physiological threshold required for active healing.MethodsThis prospective, dual-center cohort study of 733 DFU patients utilized a 20-week observation window anchored to baseline enrollment (Time Zero, T0). To isolate the independent metabolic effect of albumin from systemic inflammatory confounding, we implemented a doubly robust framework integrating generalized propensity score (GPS) weighting with restricted cubic spline (RCS) modeling. The primary endpoint was Percentage Area Reduction (PAR) at 20 weeks.ResultsBaseline albumin was identified as a significant independent driver of wound reduction (β = 3.25; 95% CI: 0.76-5.73; P = 0.01) and a protective factor against major amputation (OR = 0.89; 95% CI: 0.79-0.99; P = 0.037). RCS analysis revealed a highly significant non-linear trajectory (P for non-linearity < 0.001) with a biological inflection point at 37.9 g/L. No significant regenerative progress occurred within the 31.4-37.9 g/L stagnation plateau. Sensitivity analysis confirmed the conventional 35 g/L cutoff failed to differentiate healing outcomes (P = 0.869), resulting in 45.8% of normoalbuminemic patients being misclassified within a state of regenerative arrest. The calculated E-value of 3.40 confirms profound robustness against unmeasured confounding.ConclusionsThe conventional 35 g/L albumin threshold is clinically inadequate to sustain the metabolic demands of DFU repair. To breach the identified stagnation plateau and transition the wound bed toward active regeneration, clinicians should prioritize a new physiological target of 37.9 g/L (clinically operationalized as ≥ 38 g/L). This necessitates a strategic shift toward metabolic intensification in limb salvage protocols.
BackgroundKangfuxin Liquid, with properties of promoting tissue repair, anti-inflammation, and bacteriostasis, requires systematic evaluation regarding its efficacy and safety in adjuvant treatment of pressure ulcers.MethodsDatabases including PubMed, Embase, Cochrane Library, CNKI, and Wanfang were searched for randomized controlled trials (RCTs) published from January 2015 to June 2025, comparing Kangfuxin Liquid adjuvant therapy with standard dressing in treating stage II-III pressure ulcers. Two researchers independently screened literature, extracted data, and evaluated quality. Meta-analysis was performed using RevMan 5.4 software. Outcome indicators included wound healing rate, healing time, wound area reduction rate after 2 weeks of treatment, and adverse reaction rate.ResultsA total of 12 RCTs involving 886 patients were included, with 450 patients in the experimental group (Kangfuxin Liquid + standard dressing) and 436 in the control group (standard dressing alone). Meta-analysis showed that the experimental group had significantly higher wound healing rate [RR = 1.44, 95% CI (1.32, 1.56), P < 0.0001, I2 = 79.4%], significantly shorter healing time [MD = -6.77 days, 95% CI (-7.22, -6.32), P < 0.0001, I2 = 82.8%], significantly increased wound area reduction rate after 2 weeks of treatment [MD = 19.02%, 95% CI (17.94, 20.09), P < 0.0001, I2 = 81.7%], and a lower adverse reaction rate with no statistically significant difference [RR = 0.73, 95% CI (0.47, 1.12), P = 0.15, I2 = 83.2%]. Kangfuxin Liquid adjuvant therapy is well-tolerated with a favorable safety profile, as adverse events in the control group were mostly infection-related, while those in the KFX group were mild local irritation.ConclusionKangfuxin Liquid adjuvant therapy can significantly improve wound healing rate, shorten healing time, promote wound reduction, and ensure high safety in treating stage II-III pressure ulcers, which is worthy of clinical promotion.
ObjectiveDiabetic foot ulcers (DFUs) are a serious complication of type 2 diabetes mellitus (T2DM). Diet quality may influence DFU risk; however, evidence remains limited. This study investigated the association between overall diet quality and DFU prevalence.MethodsIn this case-control study, 390 adults with T2DM were enrolled, including 130 patients with clinically confirmed DFUs and 260 controls without DFU. Habitual dietary intake was evaluated using a validated 147-item Food Frequency Questionnaire supplemented with a recall interview. Multivariable logistic regression model was applied to examine the association between overall diet quality and DFU.ResultsMean total overall diet quality scores were significantly lower in participants with DFUs than in controls (56.3 ± 8.2 vs 61.2 ± 8.5; P < 0.001). All diet quality components, variety, adequacy, moderation, and overall balance, were also lower among DFU cases (P < .01). In fully adjusted model, the association between diet quality score and DFU was no statistically significant when analyzed as a continuous variable (OR = 0.90; 95% CI: 0.78-1.03). However, participants in the highest diet quality tertile had significantly lower odds of DFU compared with those in the lowest tertile (OR = 0.71; 95% CI: 0.49-0.99), with a significant dose-response trend observed across tertiles (P for trend = 0.031).ConclusionsDiet quality score was not significantly associated with DFU when modeled as a continuous variable; however, higher diet quality tertiles were associated with lower odds of diabetic foot ulcer, suggesting a potential protective relationship of overall dietary patterns after accounting for major sociodemographic and clinical risk factors.
