Identification of hub genes and pathways associated with cellular senescence in diabetic foot ulcers via comprehensive transcriptome analysis.

This research aimed to find important genes and pathways related to cellular senescence (CS) in diabetic foot ulcers (DFU) and to estimate the possible pathways through which CS affects diabetic foot healing. The GSE80178 dataset was acquired from the Gene Expression Omnibus (GEO) database, containing six DFU and three diabetic foot skin (DFS) samples. The limma package was used to identify differentially expressed genes (DEGs). At the same time, DEGs associated with CS (CS-DEGs) were found using the CellAge database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the CS-DEGs. A protein-protein interaction (PPI) network was built using the String database, and the cytoHubba plug-in within Cytoscape helped identify hub genes. Lastly, the miRNA-TF-mRNA regulatory network for these hub genes was established. In total, 66 CS-DEGs were obtained. These genes mainly focus on CS, Kaposi sarcoma-associated herpesvirus infection and Toll-like receptor signalling pathway. Eight hub genes were identified to regulate cell senescence in DFU, including TP53, SRC, SIRT1, CCND1, EZH2, CXCL8, AR and CDK4. According to miRNA-TF-mRNA regulatory network, hsa-mir-132-3p/SIRT1/EZH2 axis is involved in senescence cell accumulation in DFU.

Functionalised biomaterials as synthetic extracellular matrices to promote vascularisation and healing of diabetic wounds.

Diabetic foot ulcers (DFU) are a type of chronic wound that constitute one of the most serious and debilitating complications associated with diabetes. The lack of clinically efficacious treatments to treat these recalcitrant wounds can lead to amputations for those worst affected. Biomaterial-based approaches offer great hope in this regard, as they provide a template for cell infiltration and tissue repair. However, there is an additional need to treat the underlying pathophysiology of DFUs, in particular insufficient vascularization of the wound which significantly hampers healing. Thus, the addition of pro-angiogenic moieties to biomaterials is a promising strategy to promote the healing of DFUs and other chronic wounds. In this review, we discuss the potential of biomaterials as treatments for DFU and the approaches that can be taken to functionalise these biomaterials such that they promote vascularisation and wound healing in pre-clinical models.

FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers.

Diabetic foot ulcers (DFU) are a serious complication of diabetes mellitus and associated with reduced quality of life and high mortality rate. DFUs are characterized by a deregulated immune response with decreased neutrophils due to loss of the transcription factor, FOXM1. Diabetes primes neutrophils to form neutrophil extracellular traps (NETs), contributing to tissue damage and impaired healing. However, the role of FOXM1 in priming diabetic neutrophils to undergo NET formation remains unknown. Here, we found that FOXM1 regulates reactive oxygen species (ROS) levels in neutrophils and inhibition of FOXM1 results in increased ROS leading to NET formation. Next generation sequencing revealed that TREM1 promoted the recruitment of FOXM1+ neutrophils and reversed effects of diabetes and promoted wound healing in vivo. Moreover, we found that TREM1 expression correlated with clinical healing outcomes of DFUs, indicating TREM1 may serve as a useful biomarker or a potential therapeutic target. Our findings highlight the clinical relevance of TREM1, and indicates FOXM1 pathway as a novel regulator of NET formation during diabetic wound healing, revealing new therapeutic strategies to promote healing in DFUs.

Efficacy of adipose-derived mesenchymal stem cell therapy in the treatment of chronic micro- and macrovascular complications of diabetes.

Diabetes mellitus is a highly prevalent disease characterized by hyperglycaemia that damages the vascular system, leading to micro- (retinopathy, neuropathy, nephropathy) and macrovascular diseases (cardiovascular disease). There are also secondary complications of diabetes (cardiomyopathy, erectile dysfunction or diabetic foot ulcers). Stem cell-based therapies have become a promising tool targeting diabetes symptoms and its chronic complications. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are of great importance because of their abundance, non-invasive isolation and no ethical limitations. Characteristics that make ADMSCs good candidates for cell-based therapy are their wide immunomodulatory properties and paracrine activities through the secretion of an array of growth factors, chemokines, cytokines, angiogenic factors and anti-apoptotic molecules. Besides, after transplantation, ADMSCs show great ex vivo expansion capacity and differentiation to other cell types, including insulin-producing cells, cardiomyocytes, chondrocytes, hepatocyte-like cells, neurons, endothelial cells, photoreceptor-like cells, or astrocytes. Preclinical studies have shown that ADMSC-based therapy effectively improved visual acuity, ameliorated polyneuropathy and foot ulceration, arrested the development and progression of diabetic kidney disease, or alleviated the diabetes-induced cardiomyocyte hypertrophy. However, despite the positive results obtained in animal models, there are still several challenges that need to be overcome before the results of preclinical studies can be translated into clinical applications. To date, there are several clinical trials or ongoing trials using ADMSCs in the treatment of diabetic complications, most of them in the treatment of diabetic foot ulcers. This narrative review summarizes the most recent outcomes on the usage of ADMSCs in the treatment of long-term complications of diabetes in both animal models and clinical trials.

The effect of VEGF stimulation in diabetic foot ulcers: A systematic review.

Diabetic foot ulcers are a common and severe complication of diabetes mellitus, and a risk factor for amputation. Because of the vessel insufficiency in diabetic foot ulcers (DFU), vascular endothelial growth factor (VEGF) that simulates angiogenesis is of interest to promote wound healing. This systematic review evaluates the last 16 years of in-vivo studies with VEGF stimulation as a treatment for DFU, developed based on the last published systematic article. A total of 961 articles were identified through databases in two phases. 947 articles were excluded by exclusion criteria, and four articles met our inclusion criteria and were included. The effects of VEGF on wound healing were analysed in all four studies. In three studies, the VEGF-treated wounds showed statistically faster healing than those not treated with VEGF. In one study, the VEGF-treated wounds revealed a positive trend toward faster healing. Furthermore, all four studies were in favor of using VEGF, but concluded that further research is needed. These studies showed a positive trend towards faster healing and was safe when using VEGF topically on humans. Furthermore, viral particles of VEGF seem to have a systematic effect when a dose exceeding 5.0 × 109 vp pr wound. Future research in using VEGF on DFU should focus on VEGF's relevant dosage, release rate, and specific mechanism. This review inspires further research, and a consistent study design is prerequisite such that results are more homogenic and comparable. Much effort is needed to translate the results into our clinical practice.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Analysis of factors influencing the recurrence of diabetic foot ulcers.

OBJECTIVE: The aim of this study is to investigate the factors influencing the recurrence of diabetic foot ulcers (DFU) and provide guidance for reducing the recurrence rate. METHODS: A total of 211 patients diagnosed with DFU who were hospitalized and discharged from the hospital from October 2015 to January 2020 were included as the study cohort. Participants were divided into two groups according to whether the foot ulcer recurred during the 2-year follow-up period: a recurrence group (n = 84) and a non-recurrence group (n = 127). The following data were collected and analyzed for the two groups of patients: general information, foot information, laboratory indicators, diabetes comorbidities, and complications. RESULTS: (1) The overall recurrence rate of diabetic foot ulcers (DFU) within 2 years was 39.8%, indicating a high recurrence rate. (2) Significant differences were observed between the two patient groups in terms of BMI, HbA1c, TBIL, CRP, financial situation, foot deformity, first ulcer on the sole of the foot, previous amputation history, Wagner grade of the first ulcer, osteomyelitis, DFU duration (>60 days), lower limb vascular reconstruction, peripheral arterial disease (PAD), and diabetic peripheral neuropathy (DPN) (t = 2.455; Z = -1.988, -3.731, -3.618; χ2 = 7.88, 5.004, 3.906, 17.178, 16.237, 5.007, 24.642, 4.782, 29.334, 10.253). No significant differences were found for the other indicators. (3) Logistic regression analysis revealed that TBIL (OR = 0.886, p = 0.036) was a protective factor against ulcer recurrence. In contrast, PAD, previous amputation history, DPN, and the first ulcer on the sole of the foot (OR = 3.987, 6.758, 4.681, 2.405; p < 0.05 or p < 0.01) were identified as risk factors for ulcer recurrence. CONCLUSION: Early screening and preventive education targeting high-risk factors such as DPN, PAD and the initial ulcer location on the sole of the foot are essential to mitigate the high long-term recurrence rate of DFU. Furthermore, the protective role of TBIL in preventing ulcer recurrence underscores the importance of monitoring bilirubin levels as part of a comprehensive management strategy for DFU patients.

Dose-response and efficacy of 904 nm photobiomodulation on diabetic foot ulcers healing: a randomized controlled trial.

PURPOSE: This study aimed to examine the impact of a 904 nm photobiomodulation (PBM) on diabetic ulcers using varying dosages. METHODS: The study was a randomized, double-blind, placebo-controlled clinical trial that compared treatments using PBM (GaAs 904 nm 30w) with three different energy densities (4 J/cm2; 8 J/cm2; 10 J/cm2) in the healing process of non-infected diabetic foot ulcers. Eighty volunteers (48.75% female; 58.5 ± 11.1 years) were randomized into three intervention groups treated with PBM and one control group (PBM placebo). Volunteers performed up 20 interventions with PBM, either placebo or actual, in conjunction with conventional therapy, which involved dressing the wound with Helianthus annuus vegetable oil. The primary variable was the ulcer size reduction rate. RESULTS: GaAs 904 nm PBM yielded a clinically and significant ulcer size rate reduction of diabetic foot ulcers, independently of energy density range (p < 0.05). However, 10 J/cm² had 60% of completely healed ulcers and the highest proportion of patients reaching 50% of ulcer reduction rate after 5 weeks of treatment. In addition, only 10 J/cm² showed a significant difference between control group after a 10-week follow-up (p < 0.05). CONCLUSION: GaAs 904 nm PBM was effective in treating diabetic foot ulcers in this study and a dosage of 10 J/cm², after a 10-week follow-up, proved to be the most effective compared to the other groups. CLINICAL TRIAL REGISTRATION NUMBER: NCT04246814.

History of Diabetic Foot Ulcer is Associated With Increased Risk of Prosthetic Joint Infection and Sepsis After Total Joint Arthroplasty.

BACKGROUND: Diabetic foot ulcers (DFUs) are common sequelae of diabetes mellitus. Currently, the effect of DFUs on total joint arthroplasty (TJA) outcomes is sparsely evaluated. This study investigated whether DFU patients undergoing TJA increases risk of (1) prosthetic joint infections (PJI), (2) surgical site infections (SSI), (3) sepsis, (4) readmissions, and (5) revisions. METHODS: Using PearlDiver, a retrospective query from January 1, 2010 to October 31, 2020 was performed. DFU patients undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA) were included and 1:5 propensity score matched with controls using age, sex, body mass index, and various comorbidities (33,155 TKA patients [DFU = 5,529; control = 27,626]; 17,146 THA patients [DFU = 2,862; control = 14,284]). Outcomes included rates of PJI, SSI, sepsis, readmissions, and revisions. Multivariate logistical regressions calculated odds ratios (ORs), 95% confidence intervals, and P values (P < .001 as significance threshold). RESULTS: DFU increased risk of sepsis within 90 days of TKA (OR 4.59; P < .001) and THA (OR 4.87; P < .001). DFU did not increase risk of PJI at 90 days for TKA (OR 0.8; P = .1) or THA (OR 0.85; P = .34) but did by 2 years post-TKA (OR 1.51; P < .001) and THA (OR 1.55; P < .001). Risk of SSI increased in DFU cohort following TKA and THA at 90 days and 2 years and at 90-day readmissions and 2-year revisions. CONCLUSION: DFU patients undergoing TJA demonstrated increased risk of postoperative sepsis and PJI. Furthermore, DFU patients demonstrated an increased risk of SSI, readmissions, and revisions. Providers should counsel DFU patients about postoperative risks.

Podiatrist intervention could reduce the incidence of foot ulcers in patients with diabetes: a hospital survey in China.

OBJECTIVE: This study aimed to evaluate the effectiveness of podiatrists in preventing diabetic foot ulcers (DFUs) in China. METHOD: The study was a prospective investigation. A total of 300 patients were enrolled from May 2016 to May 2018 in Handan Central Hospital, China. All patients who participated in this study had been diagnosed with type 2 diabetes, according to the International Classification of Diseases (ICD-10). All participants underwent our survey, which included basic patient data and information about DFUs. The patients were followed for one year, during which time they received appropriate intervention from podiatrists, including lifestyle guidance, callus resection, tinea grinding and ingrown nail correction. At the end of the year all the patients were surveyed again. The data before and after the year were statistically compared. RESULTS: The results showed that the incidence of DFUs in patients with diabetes was significantly decreased after one year of intervention from podiatrists (20.7% versus 6.7%, p<0.001). Additionally, there was a negative correlation between the number of intervention visits and the number of DFU occurrences (Spearman correlation coefficient: -0.496, p<0.001). Furthermore, we found that 68 patients with a history of DFUs or amputation had an obviously reduced incidence of DFUs after intervention by a podiatrist (89.7% versus 27.9%, p<0.001). We also investigated other foot risk factors in all participants, such as limb neuropathy (76.3%), lower extremity vascular disease (65.7%) and foot paralysis (43.7%). CONCLUSION: The results of this study help in understanding the situation of patients with diabetes in China and to prove that standardised podiatrist intervention has an important role in inhibiting the occurrence and development of DFUs.

Timolol in the treatment of hard-to-heal wounds: a comprehensive review.

OBJECTIVE: The aims of this study were to ascertain the effectiveness and safety of the off-label use of topical timolol as an adjunct treatment for hard-to-heal (chronic) wounds. Furthermore, to review and analyse the existing literature regarding the use of topical timolol on wounds of varying aetiologies. METHOD: A systematic review of literature in the English language published between May 1961-May 2021 on the application of topical timolol for hard-to-heal wounds in adults was performed. Each research study was evaluated by two reviewers independently. Studies eligible for inclusion in the review were randomised controlled trials (RCTs), clinical trials, observational studies of at least 4 weeks' duration, case series and case studies. Search strategies were performed according to PRISMA guidelines and included MeSH terms and keyword searches. RESULTS: An initial 878 articles were identified from a search of PubMed, Ovid Medline, Embase, Cochrane, and SCOPUS. Of these, 699 were reviewed for eligibility, 19 were read in full-text, and 12 were selected for inclusion in the review. In total, two RCTs and 10 observational studies, including five case studies, were analysed. All studies demonstrated efficacy and safety of topical timolol; however, statistical analysis remained limited by lack of blinding and small sample sizes. CONCLUSION: This review concludes with all currently available evidence that topical timolol may be considered as an effective and safe adjunct treatment for refractory wounds, primarily venous leg ulcers and diabetic foot ulcers. Given the overall safety, low cost and ease of application of topical timolol, this review provides evidence in favour of off-label use and should prompt further, more rigorous studies.

Evaluation of a new low-cost negative pressure wound therapy in the treatment of diabetic foot ulcers.

OBJECTIVE: To investigate the effectiveness of a new and low-cost negative pressure wound therapy (LC-NPWT) in the treatment of diabetic foot ulcers (DFUs). METHOD: In this retrospective cohort study, patients from our inpatient clinic with Wagner grade 3 DFUs were given LC-NPWT or conventional wound dressings. The primary outcome was the wound healing rates. Complete wound healing, defined as complete re-epithelialisation of the wound, was recorded during the two months of follow-up. The definition of complete epidermis of the wound was that the skin was closed (100% re-epithelialisation), with no drainage or dressing. The secondary outcomes were the number of inpatient days and surgical procedures, and outcomes after hospital discharge. The wound score from the Bates-Jensen wound assessment tool and the levels of the inflammation factors procalcitonin (PCT), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were compared between the two groups. The Kaplan-Meier survival estimate was used to examine the cumulative wound healing rate. RESULTS: The study cohort comprised 41 patients. The two-month wound healing rate was higher in patients in the LC-NPWT group than in the control group (15/21 (71.4%) versus 8/20 (40.0%), respectively; p=0.043). At the end of the two-month follow-up period, the cumulative wound healing rate was higher in the LC-NPWT group than in the control group (p=0.032). Patients in the LC-NPWT group had fewer inpatient days (19.3±3.84 versus 25.05±4.81; p<0.001) and shorter duration of antibiotic use (32.14±3.89 days versus 36.10±5.80 days; p=0.014) than those who received conventional wound dressings. There were significant improvements in mean wound score between the LC-NPWT group and the control group (p<0.001). After one week of treatment, the blood levels of PCT (0.03±0.30ng/ml versus 0.07±0.08ng/ml; p=0.039), CRP (14.55±13.40mg/l versus 24.71±18.10mg/l; p=0.047) and ESR (42.05±29.29mm/h versus 61.65±22.42mm/h; p=0.021) were lower in patients who received LC-NPWT than those who received conventional wound dressings. CONCLUSION: LC-NPWT is effective in the treatment of DFUs and provides a cheaper alternative for patients with DFUs that could potentially alleviate the economic distress these patients endure.

Dehydrated Amnion Chorion Membrane versus standard of care for diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population. METHOD: Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC). RESULTS: The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04). CONCLUSION: In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population. DECLARATION OF INTEREST: This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

Leg dystrophic calcification as a consequence of chronic diabetic foot infection: a case report.

Foot ulceration and infection is associated with a substantial increase in morbidity and mortality in patients with diabetes. We present a clinical case of recurrent diabetic foot infection with an atypical clinical evolution. A 58-year-old male patient with type 1 diabetes and a history of bilateral Charcot foot neuroarthropathy was followed at our Diabetic Foot Clinic for an unhealed plantar foot ulcer for >1.5 years with recurrent episodes of infection. He was admitted to hospital due to foot ulcer reinfection with sepsis and ipsilateral lower limb cellulitis. The foot infection was found to be associated with an underlying abscess in the anterior compartment of the leg, with a cutaneous fistulous course with extensive alterations of an inflammatory nature. Exudate from the lesion was drained and tissue biopsied, revealing Serratia marcescens and Klebsiella oxytoca with dystrophic calcification (DC). Surgical excision of dystrophic tissue with debridement of the fistulous tracts was performed. The excised material corroborated the presence of fibroadipose connective tissue with marked DC, as well as areas of mixed inflammation compatible with a chronic infectious aetiology. Targeted long-term antibiotic therapy was implemented, for a total of six weeks, with a favourable clinical evolution and complete closure of the lesion at the final follow-up. DC results from calcium deposition in degenerated tissues without evidence of systemic mineral imbalance and is a potential cause of non-healing ulcers. Few cases of DC have been reported in diabetic foot patients and its treatment remains challenging and controversial. A longer follow-up period is necessary to verify the effectiveness of our approach.

Treatment of hard-to-heal wounds in ischaemic lower extremities with a novel fish skin-derived matrix.

OBJECTIVE: To evaluate the efficacy of treatment of hard-to-heal wounds of patients with ischaemia of the lower extremities, and compare an omega-3 wound matrix product (Kerecis, Iceland) with a standard dressing. METHOD: A single-centre, prospective, randomised, controlled clinical trial of patients with hard-to-heal wounds following three weeks of standard care was undertaken. The ischaemic condition of the wound was confirmed as a decreased transcutaneous oxygen pressure (TcPO2) of <40mmHg. After randomising patients into either a case (omega-3 dressing) or a control group (standard dressing), the weekly decrease in wound area over 12 weeks and the number of patients that achieved complete wound closure were compared between the two groups. Patients with a TcPO2 of ≤32mmHg were taken for further analysis of their wound in a severe ischaemic context. RESULTS: A total of 28 patients were assigned to the case group and 22 patients to the control group. Over the course of 12 weeks, the wound area decreased more rapidly in the case group than the control group. Complete wound healing occurred in 82% of patients in the case group and 45% in the control group. Even in patients with a severe ischaemic wound with a TcPO2 value of <32 mmHg, wound area decreased more rapidly in the case group than the control group. The proportions of re-epithelialised area in the case and control groups were 80.24% and 57.44%, respectively. CONCLUSION: Considering the more rapid decrease in wound area and complete healing ratio in the case group, application of a fish skin-derived matrix for treating lower-extremity hard-to-heal wounds, especially with impaired vascularity, would appear to be a good treatment option.

Use of hypothermically stored amniotic membrane on diabetic foot ulcers: a multicentre retrospective case series.

OBJECTIVE: The aim of this retrospective case series was to report on the outcomes of diabetic foot ulcers (DFUs) managed with hypothermically stored amniotic membrane (HSAM). METHOD: Deidentified case data of patients who received HSAM were obtained from wound care sites across the US. Data were collected, beginning at the first patient visit to the wound care site (first presentation), at the visit in which the first HSAM application occurred (baseline), and at each subsequent visit over 12 weeks of treatment (follow-up). All patients received standard of care (SoC) between first presentation and baseline. RESULTS: Of the 50 patients in the study, 68% were male. Mean age of the entire cohort was 66.7 years. Of the DFUs, 88% were present for <6 months at first presentation. Mean wound area was 3.5cm2, and mean percentage area reduction was -68.3% from first presentation to baseline. The mean number of HSAM applications was 5.5, and mean number of days between applications was 7.5. A >60% area reduction was attained in 96.0% of DFUs, and 78% attained complete wound closure (CWC) by week 12. The median time to CWC was 55 days. CONCLUSION: The results of this retrospective case series suggest positive outcomes for DFUs managed with HSAM. A reduction in time to CWC may lead to lesser financial burden and improved quality of life for DFU patients. DECLARATION OF INTEREST: The authors have no conflicts of interest.

Capturing How the Accelerometer Measured Physical Activity Profile Differs in People with Diabetic Foot Ulceration.

Diabetic Foot Ulcers (DFUs) are a major complication of diabetes, with treatment requiring offloading. This study aimed to capture how the accelerometer-assessed physical activity profile differs in those with DFUs compared to those with diabetes but without ulceration (non-DFU). Participants were requested to wear an accelerometer on their non-dominant wrist for up to 8days. Physical activity outcomes included average acceleration (volume), intensity gradient (intensity distribution), the intensity of the most active sustained (continuous) 5-120 min of activity (MXCONT), and accumulated 5-120 min of activity (MXACC). A total of 595 participants (non-DFU = 561, DFU = 34) were included in the analysis. Average acceleration was lower in DFU participants compared to non-DFU participants (21.9 mg [95%CI:21.2, 22.7] vs. 16.9 mg [15.3, 18.8], p < 0.001). DFU participants also had a lower intensity gradient, indicating proportionally less time spent in higher-intensity activities. The relative difference between DFU and non-DFU participants was greater for sustained activity (MXCONT) than for accumulated (MXACC) activity. In conclusion, physical activity, particularly the intensity of sustained activity, is lower in those with DFUs compared to non-DFUs. This highlights the need for safe, offloaded modes of activity that contribute to an active lifestyle for people with DFUs.

A Multi-Faceted Digital Health Solution for Monitoring and Managing Diabetic Foot Ulcer Risk: A Case Series.

INTRODUCTION: Diabetic foot ulcers (DFU) are a devastating complication of diabetes. There are numerous challenges with preventing diabetic foot complications and barriers to achieving the care processes suggested in established foot care guidelines. Multi-faceted digital health solutions, which combine multimodal sensing, patient-facing biofeedback, and remote patient monitoring (RPM), show promise in improving our ability to understand, prevent, and manage DFUs. METHODS: Patients with a history of diabetic plantar foot ulcers were enrolled in a prospective cohort study and equipped with custom sensory insoles to track plantar pressure, plantar temperature, step count, and adherence data. Sensory insole data enabled patient-facing biofeedback to cue active plantar offloading in response to sustained high plantar pressures, and RPM assessments in response to data trends of concern in plantar pressure, plantar temperature, or sensory insole adherence. Three non-consecutive case participants that ultimately presented with pre-ulcerative lesions (a callus and/or erythematous area on the plantar surface of the foot) during the study were selected for this case series. RESULTS: Across three illustrative patients, continuous plantar pressure monitoring demonstrated promise for empowering both the patient and provider with information for data-driven management of pressure offloading treatments. CONCLUSION: Multi-faceted digital health solutions can naturally enable and reinforce the integrative foot care guidelines. Multi-modal sensing across multiple physiologic domains supports the monitoring of foot health at various stages along the DFU pathogenesis pathway. Furthermore, digital health solutions equipped with remote patient monitoring unlock new opportunities for personalizing treatments, providing periodic self-care reinforcement, and encouraging patient engagement-key tools for improving patient adherence to their diabetic foot care plan.

Stepping Forward: A Scoping Systematic Literature Review on the Health Outcomes of Smart Sensor Technologies for Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) pose a significant challenge in diabetes care, demanding advanced approaches for effective prevention and management. Smart insoles using sensor technology have emerged as promising tools to address the challenges associated with DFU and neuropathy. By recognizing the pivotal role of smart insoles in successful prevention and healthcare management, this scoping review aims to present a comprehensive overview of the existing evidence regarding DFU studies related to smart insoles, offloading sensors, and actuator technologies. This systematic review identified and critically evaluated 11 key studies exploring both sensor technologies and offloading devices in the context of DFU care through searches in CINAHL, MEDLINE, and ScienceDirect databases. Predominantly, smart insoles, mobile applications, and wearable technologies were frequently utilized for interventions and patient monitoring in diabetic foot care. Patients emphasized the importance of these technologies in facilitating care management. The pivotal role of offloading devices is underscored by the majority of the studies exhibiting increased efficient monitoring, prevention, prognosis, healing rate, and patient adherence. The findings indicate that, overall, smart insoles and digital technologies are perceived as acceptable, feasible, and beneficial in meeting the specific needs of DFU patients. By acknowledging the promising outcomes, the present scoping review suggests smart technologies can potentially redefine DFU management by emphasizing accessibility, efficacy, and patient centricity.

Two-Pronged Microbe Delivery of Nitric Oxide and Oxygen for Diabetic Wound Healing.

Chronic inflammation and hypoxia in the microenvironment of diabetic foot ulcers (DFUs) can result in sustained vascular impairment, hindering tissue regeneration. While both nitric oxide and oxygen have been shown to promote wound healing in DFUs through anti-inflammatory and neovascularization, there is currently no available therapy that delivers both. We present a novel hydrogel consisting of Weissella and Chlorella, which alternates between nitric oxide and oxygen production to reduce chronic inflammation and hypoxia. Further experiments indicate that the hydrogel accelerates wound closure, re-epithelialization, and angiogenesis in diabetic mice and improves the survival of skin grafts. This dual-gas therapy holds promise as a potential treatment option for the management of diabetic wounds.