Surgical debridement and maggot debridement therapy can survive patient with diabetic foot ulcer after foot trauma: A case report.

INTRODUCTION AND IMPORTANCE: Diabetic foot ulcers, a common issue associated with diabetes, can pose challenges in treatment, especially when they do not respond to traditional therapies. Maggot therapy, known as larval therapy, has surfaced as a substitute approach for managing stubborn wounds. CASE PRESENTATION: A 42-year-old male with a history of type 2 diabetes and peripheral neuropathy presents at the clinic with a long-lasting sore on the bottom of his right foot. The individual reveals that the ulcer has persisted for multiple months and has shown no improvement despite trying different remedies like creams and dressings. CLINICAL DISCUSSION: Diabetic foot ulcers are significant complications associated with diabetes, commonly triggered by neuropathy, peripheral artery disease, and impaired wound healing mechanisms. These ulcers can result in severe infections, amputations, and reduced quality of life for those affected. CONCLUSION: Maggot therapy arises as a valuable additional option for chronic ulcers in diabetic patients, providing a secure and efficient method for cleaning wounds and promoting healing.

The incidence of lower extremity amputation and its associated risk factors in patients with diabetic foot ulcers: A meta-analysis.

This study analysed the incidence of lower extremity amputation and its associated risk factors in patients with diabetic foot ulcers. This study systematically searched both Chinese and English databases, including CNKI, Wanfang, VIP, PubMed, EMBASE and Web of Science, to identify cohort studies related to lower extremity amputation and associated risk factors in patients with diabetic foot ulcers up to October 2023. The patients were stratified based on whether they underwent lower extremity amputation, and relevant data, including basic information, patient characteristics, complications, comorbidities and pertinent laboratory test data, were extracted from the included studies. The literature quality assessment in this study utilized the Newcastle-Ottawa Scale to screen for high-quality literature, resulting in the inclusion of 16 cohort studies, all of which were of at least moderate quality. Meta-analysis of outcome indicators was conducted using the Stata 14.0 software. The results indicate that the overall amputation rate of lower extremities in patients with diabetic foot ulcers is 31% (0.25, 0.38). Among the 16 variables evaluated, gender (male), smoking history, body mass index (BMI), hypertension, cardiovascular disease, kidney disease, white blood cell count, haemoglobin and albumin levels were found to be correlated with the occurrence of lower extremity amputation in patients with diabetic foot ulcers. However, no significant correlation was observed between age, diabetes type, duration of diabetes, stroke, glycosylated haemoglobin, creatinine and total cholesterol levels and lower extremity amputation in patients with diabetic foot ulcers. This meta-analysis indicates that the overall amputation rate in patients with diabetic foot ulcers is 31%. Factors such as gender (male), smoking history, high BMI, hypertension, cardiovascular disease, kidney disease, white blood cell count, haemoglobin and albumin levels are identified as significant risk factors for lower extremity amputation in diabetic foot ulcer patients. These findings suggest that attention should be focused on these risk factors in patients with diabetic foot ulcers to reduce the risk of lower extremity amputation. Therefore, preventive and intervention measures targeting these risk factors are of significant importance in clinical practice. (Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42024497538]).

Relaxation intervention to improve diabetic foot ulcer healing: protocol for a pilot study with a nested qualitative study.

OBJECTIVE: A mixed-methods approach nested in a pilot three-arm randomised controlled trial (RCT) was conducted to evaluate the feasibility and acceptability of an intervention of progressive muscle relaxation with guided imagery (experimental group) compared to a neutral guided imagery placebo (active control group) and a group that did not receive any psychological intervention (passive control group). The purpose was to inform a future definitive RCT that will test its effectiveness. Qualitatively, this study examined patients and health professionals' perspectives regarding the relaxation intervention, in order to assess the acceptability and applicability of relaxation as an adjuvant therapy. METHOD: Participants must have had a diagnosis of diabetes and diabetic foot disease; one or two active hard-to-heal ulcers at the time of the assessment; and clinical levels of stress or anxiety or depression. Participants were randomised and assessed at three timepoints after the first hospital consultation for hard-to-heal diabetic foot ulcer (DFU). RESULTS: Rates of eligibility, recruitment, refusal, adherence to study protocol, participation in follow-up and dropout, and patients' satisfaction with the relaxation intervention were assessed as primary outcomes. Secondary outcomes were DFU healing; patients' DFU-related quality of life; physical and mental quality of life; perceived stress; emotional distress; adherence to DFU care; perceptions of DFU; as well as arterial systolic/diastolic pressure and heart rate. CONCLUSION: The results of this pilot study contributed to clarification and better elucidation of the benefits of relaxation techniques regarding patients' HRQoL and DFU healing. DECLARATION OF INTEREST: Funding: This study was conducted at the Psychology Research Centre (CIPsi/UM) School of Psychology, University of Minho, Portugal and supported by the Foundation for Science and Technology (FCT) through the Portuguese State Budget (UIDB/01662/2020) and by a PhD fellowship from FCT assigned to GF (SFRH/BD/131780/2017) and an FCT grant (PTDC/PSI-GER/28163/2017) assigned to MGP. The authors have no conflicts of interest to declare.

A single dose of VEGF-A circular RNA sustains in situ long-term expression of protein to accelerate diabetic wound healing.

Diabetic foot ulcer (DFU), which is characterised by damage to minute blood vessels or capillaries around wounds, is one of the most serious and dreaded complications of diabetes. It is challenging to repair chronic non-healing DFU wounds. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and promotes wound healing in DFU. However, it is difficult to sustainably deliver VEGF to the wound site owing to its poor stability and easy degradation. To overcome this challenge, lipid nanoparticles (LNP) encapsulating circular RNA (circRNA) encoding VEGF-A have been developed to continuously generate and release VEGF-A and accelerate diabetic wound healing. First, VEGF-A circRNA was synthesized using group I intron autocatalysis strategy and confirmed by enzyme digestion, polymerase chain reaction, and sequencing assay. VEGF-A circRNA was encapsulated in ionizable lipid U-105-derived LNP (U-LNP) using microfluidic technology to fabricate U-LNP/VEGF-A circRNA. For comparison, a commercially ionizable lipid ALC-0315-derived LNP (A-LNP) encapsulating circRNA (A-LNP/circRNA) was used. Dynamic light scattering and transmission electron microscopy characterization indicated that U-LNP/circRNA had spherical structure with an average diameter of 108.5 nm, a polydispersity index of 0.22, and a zeta potential of -3.31 mV. The messenger RNA (mRNA) encapsulation efficiency (EE%) of U-LNP was 87.12%. In vitro transfection data confirmed better stability and long-term VEGF-A expression of circRNA compared with linear mRNA. Assessment of cytotoxicity and innate immunity further revealed that U-LNP/circRNA was biocompatible and induced a weak congenital immune response. Cell scratch and angiogenesis tests demonstrated the bioactivity of U-LNP/VEGF-A circRNA owing to its VEGF-A expression. In situ bioluminescence imaging of firefly luciferase (F-Luc) probe and ELISA demonstrated that circRNA had long-term and strong expression of VEGF-A in the first week, and a gradual decrease in the next week at the wound site and surrounding areas. Finally, a diabetic mouse model was used to validate the healing effect of U-LNP/VEGF-A circRNA formulation. The results showed that a single dose of U-LNP/VEGF-A circRNA administered by dripping resulted in almost complete wound recovery on day 12, which was significantly superior to that of U-LNP/VEGF-A linear mRNA, and it also outperformed recombinant human vascular endothelial growth factor (rhVEGF) injection and A-LNP/circRNA dripping. Histological analysis confirmed the healing efficiency and low toxicity of U-LNP/VEGF-A circRNA formulation. Together, VEGF-A circRNA delivered by U-105-derived LNP showed good performance in wound healing, which was ascribed to the long-term expression and continuous release of VEGF-A, and has potential applications for the treatment of diabetic foot ulcer wounds.

Diabetic foot self-care knowledge and practice among patients with diabetes attending diabetic clinic in the Gambia.

Diabetic foot ulcer is the most common complication causing lots of admissions among diabetic patients. Understanding patients' level of foot self-care knowledge, practice and associated factors is important for planning interventions to control and prevent diabetic foot complications. This study aimed to assess the level of knowledge and practice of foot self-care among diabetic patients attending diabetic clinics in The Gambia. Two hundred and seventeen patients attending diabetic clinics in two public hospitals were selected using a successive sampling technique. Data were collected using a validated interviewer-administered questionnaire. Descriptive statistics were used to summarize the demographic and clinical data. Multivariate logistic regression was used to identify factors associated with foot self-care knowledge and practice. The findings showed a poor level of foot self-care knowledge (n = 114; 52.5%) and practice (n = 149; 68.7%). Patients' educational level was statistically significantly association with diabetic foot self-care knowledge (p = 0.02). Diabetic foot ulcer history (aOR = 0.23, 95% CI: 0.08-0.63; p < 0.001), diabetic hospitalization (aOR = 2.41, 95% CI: 1.23-4.75, p = 0.01) and diabetic foot care education (aOR = 2.65, 95% CI: 1.39-5.06, p < 0.001) were statistically significantly associated with foot self-care practice. The poor diabetic foot self-care knowledge and practice among these patients emphasize the need for a diabetic health education program in these clinics.

Comprehensive infectious diabetic foot ulcer repair through multiple dressing methods, maggot therapy, and vacuum therapy after amputation: A case report study.

INTRODUCTION AND IMPORTANCE: Diabetic foot ulcers are a prevalent and challenging issue among diabetes patients, frequently leading to notable health concerns and reduced quality of life. Effectively addressing diabetic foot ulcers necessitates a comprehensive treatment strategy. CASE PRESENTATION: The 69-year-old patient with Type 2 diabetes, complicated by illiteracy and poor glycemic control, developed a foot wound that escalated to cellulitis and abscess due to diabetes and peripheral vascular disease. After angioplasty and midfoot amputation, treatment focused on wound healing with antibiotics, local anesthesia, larval therapy, vacuum-assisted closure (VAC), platelet-rich plasma (PRP) injections, and specialized dressings. A multidisciplinary team approach facilitated successful wound healing and functional improvement, highlighting the importance of comprehensive care and innovative treatments in complex diabetic foot ulcers. DISCUSSION: Diabetic foot ulcers, a frequent complication of diabetes, present notable hurdles in treatment and care. Comprehensive strategies are typically essential for managing these ulcers efficiently and averting additional issues. Recently, there has been increasing attention towards employing various dressing techniques, maggot therapy, and vacuum therapy as integral components of a holistic diabetic foot ulcer treatment approach. CONCLUSION: Employing a comprehensive method involving various dressing techniques, maggot therapy, and vacuum therapy for diabetic foot ulcers can significantly boost wound healing, curb infections, and lower the chances of additional complications.

The impact of COVID-19 on the care of diabetic foot ulcers: A scoping review.

AIM: The aims and objectives of this scoping review were to conduct a systematic search of the literature to identify the nature and extent of the research evidence to which the COVID-19 pandemic impacted and disrupted the care of Diabetic Foot Ulcers (DFU) and the subsequent impact on patient outcomes. Secondly, to identify transformation in models of care and service delivery, adoption of innovative technologies and new models of service innovations, including modalities such as telehealth that were adopted during the pandemic. METHODS: This systematic scoping review was conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping reviews (PRISMA-ScR). RESULTS: Nineteen papers were included. These studies explored aspects of care for DFUs during the COVID-19 pandemic. The focus of these studies ranged from exploring new modalities of care such as telehealth, reporting of clinical outcomes, development of triage systems and patient behaviors during COVID-19. CONCLUSION: Ten of twelve studies reported on DFU outcomes and reported a worsening of outcomes compared to pre-pandemic times. Reduced DFU presentations, alongside an increase in urgent hospitalisations and amputation, were key themes that emerged from this review. More high-quality evidence is needed to establish any longer-lasting effects of the Covid-19 pandemic on people living with DFU. Further, there is a lack of evidence relating to the feasibility and success of telemedicine and limited data on changes to service delivery, including triage systems in this patient cohort.

Effect of Ozone Therapy on Diabetes-related Foot Ulcer Outcomes: A Systematic Review and Meta-analysis.

PURPOSE: This study aimed to assess the effectiveness of ozone therapy in treating Diabetes-related Foot Ulcer (DFU) and its outcomes. METHODS: A systematic search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and ProQuest databases for published studies evaluating the use of ozone as an adjunct treatment for DFU, from inception to December 21, 2022. The primary outcome measure was the change in wound size after the intervention compared to pretreatment. Secondary outcomes included time to complete ulcer healing, number of healed patients, adverse events, amputation rates, and hospital length of stay. Quantitative data synthesis for the meta-analysis was performed using a random-effects model and generic inverse variance method, while overall heterogeneity analysis was conducted using a fixed-effects model. Interstudy heterogeneity was assessed using the I2 index (<50%) and the Cochrane Q statistic test. Sensitivity analysis was performed using the leave-one-out method. RESULTS: The meta-analysis included 11 studies comprising 960 patients with DFU. The results demonstrated a significant positive effect of ozone therapy on reducing foot ulcer size (Standardized Mean Difference (SMD): -25.84, 95% CI: -51.65 to -0.04, p = 0.05), shortening mean healing time (SMD: -38.59, 95% CI: -51.81 to -25.37, p < 0.001), decreasing hospital length of stay (SMD: -8.75, 95% CI: -14.81 to -2.69, p < 0.001), and reducing amputation rates (Relative Risk (RR): 0.46, 95% CI: 0.30-0.71, p < 0.001), compared to standard treatment. CONCLUSION: This meta-analysis indicates that ozone therapy has additional benefits in expediting complete DFU healing, reducing the amputation rates, and decreasing hospital length of stay, though its effects do not differ from standard treatments for complete ulcer resolution. Further research is needed to address the heterogeneity among studies and to better understand the potential beneficial effects of ozone therapy.

The interplay between patients and healthcare professionals in a cross-sectoral setting in connection with the treatment and care of patients with diabetic foot ulcers: a realistic evaluation.

BACKGROUND: Diabetes-related lower extremity complications such as diabetic foot ulcer (DFU) are a global disability burden. Treatment and care for patients with DFU call for a multisectoral approach that incorporates interdisciplinary care pathways. We aimed to explore the interplay between patients with DFU and healthcare professionals in cross-sectoral settings that address treatment and care and to determine "what works, for whom, and under what circumstances". METHOD: The study was designed as a realistic evaluation. The data were generated from September 2022 to March 2023 and drew upon approximately 60 h of participant observation of 14 patients during the treatment and care of DFUs in their homes (primary care) and/or at outpatient clinics (wound specialist clinics in a hospital setting) in a Danish cross-sectoral setting. The Standards for Reporting Qualitative Research (SRQR) were applied in this study. RESULTS: We identified three illuminating themes that described the interplay between patients with DFU and related healthcare professionals representing both primary and secondary health care systems: (1) humour is a relationship-enhancing element between nurses and patients; (2) support from patients' coping strategies promotes patient-centeredness and collaboration; and (3) patients and professionals occupy unnegotiated identity roles. CONCLUSION: Our study led to a refined programme theory developed through the realistic evaluation process that allows us to propose an answer to the problem of "what works, for whom, and under what circumstances". The interplay between patients with DFU and healthcare professionals in a cross-sectoral setting for treatment and care is characterised by the use of humour as a relation-enhancing element and by improving support for patient coping strategies, which encourages healthcare professionals to promote health literacy. Future research should examine strategies for negotiating identity roles between patients with DFU and healthcare professionals to enhance collaboration, patient health literacy, and health promotion in cross-sectoral healthcare settings.

Efficacy of autologous platelet-rich plasma gel in patients with hard-to-heal diabetic foot ulcers: a multicentre study in Japan.

OBJECTIVE: To evaluate the healing outcome of a platelet-rich plasma (PRP) gel prepared using TKKT01 (a wound care device to prepare the PRP gel) in patients with hard-to-heal diabetic foot ulcers (DFUs) and who showed an inadequate response to ≥4 weeks of standard of care (SoC). METHOD: This open-label, single-arm, multicentre study was conducted in 15 centres in Japan. Eligible patients received PRP gel treatment twice a week for eight weeks, followed by a final evaluation after the completion of week 8 (day 57). The primary endpoint was the percentage of patients who achieved ≥50% reduction in wound radius at the final evaluation (achievement criterion, ≥60% of patients). Secondary endpoints included: wound area and volume reduction rates; time to possible wound closure by secondary intention; time to possible wound closure using a relatively simple procedure (e.g., skin graft and suture); and safety at the final evaluation. RESULTS: A total of 54 patients were included in the full analysis set, with 47 patients included in the per protocol set; the primary endpoint was met in 38/47 (80.9%) (95% confidence interval: 66.7-90.9%) patients who achieved ≥50% wound radius reduction at the final evaluation. High rates of wound area (72.8%) and volume (92.7%) reduction were observed at the final evaluation. The median time to possible wound closure by secondary intention and by use of a relatively simple procedure was 57 and 43 days, respectively. Complete wound closure at the final evaluation was achieved in 27 (57.4%) patients. No safety concerns were raised. CONCLUSION: In this study, the efficacy and safety of PRP gel treatment with TKKT01 in patients with hard-to-heal DFUs in Japan were confirmed by our findings. DECLARATION OF INTEREST: This study was funded by Rohto Pharmaceutical Co., Ltd., Japan. NO has been paid a consulting fee by Rohto Pharmaceutical Co., Ltd. KH is the Chief Medical Officer of Rohto Pharmaceutical. Co., Ltd. The other authors have no conflict of interest to declare.

Correlation of ankle-wrist pressure index with ankle-brachial pressure index to assess lower limb perfusion in diabetic foot ulcer: a pilot study.

OBJECTIVE: The presence of peripheral artery disease (PAD) in patients with diabetic foot ulcers (DFUs) is a significant risk factor for chronicity and amputation. Ankle-brachial pressure index (ABPI) is a screening tool for PAD. Brachial systolic pressure measurement, used as a denominator in the calculation of ABPI, produces inaccurate results in patients with obesity and the presence of heavy clothing. The wrist, however, is easily accessible, and the ankle-wrist pressure index (AWPI), if comparable with ABPI, may be useful in screening selected patients. This study aimed to assess the efficacy of AWPI in diagnosing perfusion in DFUs and compare it to ABPI in patients with DFUs. METHOD: ABPI and AWPI were calculated by measuring systolic blood pressure in the arteries of the ankle, arm and wrist with a handheld Doppler. Actual perfusion was determined by the presence or absence of PAD by duplex ultrasound. RESULTS: A total of 46 lower extremities in 41 patients were studied. The prevalence of PAD was 61%. Duplex ultrasound confirmed that the sensitivity of ABPI and AWPI in detecting PAD in patients with DFUs was 67.9% and 71.4% respectively, whereas the specificity of ABPI and AWPI was 94.4% and 88.9% respectively. On receiver operating characteristic analysis, the area under the curve of ABPI and AWPI was 0.804 and 0.795, respectively. A statistically significant positive correlation between ABPI and AWPI was found (r=0.986; p<0.001). CONCLUSION: There was a good correlation between ABPI and AWPI over a wide range of values. ABPI and AWPI may have a similar role in predicting perfusion in patients with DFUs. AWPI could be used in place of ABPI in selected patients in whom measuring ABPI may be difficult. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare.

Electrical Stimulating Redox Membrane Incorporated with PVA/Gelatin Nanofiber for Diabetic Wound Healing.

Chronic wounds adversely affect the quality of life. Although electrical stimulation has been utilized to treat chronic wounds, there are still limitations to practicing it due to the complicated power system. Herein, an electrostimulating membrane incorporated with electrospun nanofiber (M-sheet) to treat diabetic wounds is developed. Through the screen printing method, the various alternate patterns of both Zn and AgCl on a polyurethane substrate, generating redox-mediated electrical fields are introduced. The antibacterial ability of the patterned membrane against both E. coli and S. aureus is confirmed. Furthermore, the poly(vinyl alcohol) (PVA)/gelatin electrospun fiber is incorporated into the patterned membrane to enhance biocompatibility and maintain the wet condition in the wound environment. The M-sheet can improve cell proliferation and migration in vitro and has an immune regulatory effect by inducing the polarization of macrophage to the M2 phenotype. Finally, when applied to a diabetic skin wound model, the M-sheet displays an accelerated wound healing rate and enhances re-epithelialization, collagen synthesis, and angiogenesis. It suggests that the M-sheet is a simple and portable system for the spontaneous generation of electrical stimulation and has great potential to be used in the practical wound and other tissue engineering applications.

METTL3-mediated NDUFB5 m6A modification promotes cell migration and mitochondrial respiration to promote the wound healing of diabetic foot ulcer.

BACKGROUND: Diabetic foot ulcer (DFU) is the most devastating complication of diabetes mellitus (DM) and plays a major role in disability and death in DM patients. NADH: ubiquinone oxidoreductase subunit B5 (NDUFB5) plays an important role in maintaining mitochondrial respiration, but whether it is involved in regulating the progression of advanced glycation end products (AGEs)-mediated DFU is still unclear. METHODS: Firstly, the role of AGEs on cell viability, migration, and mitochondrial respiration in human umbilical vein endothelial cells (HUVECs) was explored in vitro. Next, NDUFB5 expression was detected in human samples and AGEs-treated HUVECs, and NDUFB5's effect on AGEs-induced HUVECs injury and skin wound in diabetic mice was further clarified. In addition, the role of m6A modification mediated by methyltransferase-like 3 (METTL3) in regulating NDUFB5 expression and AGEs-induced HUVECs injury was investigated. RESULTS: NDUFB5 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs, whereas mitochondrial fusion promoter M1 facilitated cell viability, migration, and mitochondrial oxiadative respiration in NDUFB5 knockdown HUVECs. Meanwhile, NDUFB5 promotes skin wound healing in diabetic mice. Besides, METTL3-mediated m6A modification and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) enhanced NDUFB5 expression in HUVECs. Furthermore, METTL3 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs by increasing NDUFB5. CONCLUSION: METTL3-mediated NDUFB5 m6A modification inhibits AGEs-induced cell injury in HUVECs. METTL3 and NDUFB5 might serve as potential targets for DFU therapy in the future.

Efficacy of tibial cortex transverse transport in treating diabetic foot ulcer and its effect on serum omentin-1 and irisin levels.

OBJECTIVE: Diabetic foot ulcer (DFU) is a common and debilitating complication of diabetes that is associated with an increased risk of lower-limb amputation and a reduced life expectancy. Tibial cortex transverse transport (TTT) has become a newly alternative surgical method to facilitate ulcer healing and prevent lower limb amputation. Herein, we investigated the efficacy of TTT in treating DFU and changes of serum omentin-1 and irisin levels. METHODS: This study prospectively recruited 52 consecutive patients with DFU who were treated with TTT. The follow-up was performed weekly during the first 12 weeks postoperatively and every 3 months until 1 year after TTT. The serum levels of vascular endothelial growth factor (VEGF), omentin-1, and irisin in DFU patients undergoing TTT were determined by ELISA methods on the preoperative 1st day, postoperative 2nd week and 4th week. RESULTS: The wound healing rate was 92.3% (48/52) at the 1-year follow-up. The visual analog scale (VAS) pain scores of patients showed a significant reduction at the 4th week after TTT (p < 0.001). The dorsal foot skin temperature, ankle brachial index, and dorsal foot blood flow of patients were significantly increased at the 4th week after TTT (p < 0.001). Results of ELISA methods showed the serum levels of VEGF, omentin-1, and irisin on the 2nd week and 4th week after TTT were notably elevated compared to the levels determined on the preoperative 1st day (p < 0.001). The serum levels of VEGF, omentin-1, and irisin on the 4th week after TTT were also significantly higher than the levels determined on the 2nd week after TTT (p < 0.001). CONCLUSION: TTT could promote the wound healing and reduce the risk of lower limb amputation, demonstrating promising clinical benefits in the treatment of DFU. Increased expressions of serum proangiogenic factors including VEGF, omentin-1, and irisin were noted in the early stage after TTT, which may provide a new mechanism of TTT promoting wound heal.

Development of a research agenda for medical grade footwear in the Netherlands: A multidisciplinary multiphase project to determine the key research questions to advance scientific knowledge in the field.

BACKGROUND: The field of medical grade footwear is dynamic. Originally, a field where individual knowledge, expertise and skills determined the footwear and its outcomes, now becoming a more evidence-based and data-driven field with protocols and systems in place to create appropriate footwear. However, scientific evidence concerning medical grade footwear is still limited. Evidently, all stakeholders, from patients to pedorthists to rehabilitation physicians, will profit from a larger evidence-base in this field. A widely supported research agenda is an essential first step to advance and facilitate new knowledge. METHODS: We formed a multidisciplinary team and followed the methodology from Dutch medical societies for the development of a research agenda on medical grade footwear. This consisted of seven steps: (1) inventory of relevant questions with users and professionals; (2) analyses of responses; (3) analyses of existing knowledge and evidence; (4) formulating research questions; (5) prioritising research questions by users and professionals; (6) finalising the research agenda and (7) implementing the research agenda. RESULTS: In phase 1, 109 participants completed a survey, including 50% pedorthists, 6% rehabilitation physicians and 3% users. Participants provided 228 potential research questions. In phases 2-4, these were condensed to 65 research questions. In phase 5, 152 participants prioritised these 65 research questions, including 50% pedorthists, 13% rehabilitation physicians and 9% users. In phase 6, the final research agenda was created, with 26 research questions, categorised based on the International Classification of Functioning Disability and Health 'process description assistive devices'. In phase 7, an implementation meeting was held with over 50 stakeholders (including users and professionals), resulting in seven applications for research projects based on one or more research questions from the research agenda. CONCLUSIONS: This research agenda structures and guides knowledge development within the field of medical grade footwear in the Netherlands and elsewhere. We expect that this will help to stimulate the field to tackle the research questions prioritised and with that to advance scientific knowledge in this field.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

AIM: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers.

The aim of this study was to investigate dermal delivery of the new active pharmaceutical ingredient (API) TOP-N53 into diabetic foot ulcer using an in vitro wound model consisting of pig ear dermis and elucidate the impact of drug formulation and wound dressing taking into consideration clinical relevance and possible bacterial infection. Different formulation approaches for the poorly water-soluble API including colloidal solubilization, drug micro-suspension and cosolvent addition were investigated; moreover, the effect of (micro-)viscosity of hydrogels on delivery was assessed. Addition of Transcutol® P as cosolvent to water improved solubility and was significantly superior to all other approaches providing a sustained three-day delivery that reached therapeutic drug levels in the tissue. Solubilization in micelles or liposomes, on the contrary, did not boost delivery while micro-suspensions exhibited sedimentation on the tissue surface. Microbial contamination was responsible for considerable metabolism of the drug leading to tissue penetration of metabolites which may be relevant for therapeutic effect. Use of hydrogels as primary wound dressing under semi-occlusive conditions significantly reduced drug delivery in a viscosity-dependent fashion. Micro-rheologic analysis of the gels using diffusive wave spectroscopy confirmed the restricted diffusion of drug particles in the gel lattice which correlated with the obtained tissue delivery results. Hence, the advantages of hydrogel dressings from the applicatory characteristic point of view must be weighed against their adverse effect on drug delivery. The employed in vitro wound model was useful for the assessment of drug delivery and the development of a drug therapy concept for chronic diabetic foot ulcer in the home care setting. Mechanistic insights about formulation and dressing performance may be applied to drug delivery in other skin conditions such as digital ulcer.

Prototyping and Experimental Analysis of Active Offloading Footwear for Patients With Diabetes Using an Array of Magnetorheological Fluid-Based Modules.

BACKGROUND: Diabetic foot ulceration is a serious challenge worldwide which imposes an immense risk of lower extremity amputation and in many cases may lead to the death. The presented work focuses on the offloading requirements using an active approach and considers the use of magnetorheological fluid-based modules to redistribute high plantar pressures (PPs). METHODS & RESULTS: Experimentation validated a single module with a threshold peak pressure of 450 kPa, whereas an offloading test with a three-module array and complete footwear validated a maximum pressure reduction of 42.5% and 34.6%, respectively. CONCLUSION: To our knowledge, no such active and electrically controllable offloading footwear has been reported yet that has experimentally demonstrated PP reduction of more than 30% over the offloading site.

Correlation between initial serum 25-hydroxyvitamin D and granulation growth in diabetic foot ulcers.

OBJECTIVE: To determine the correlation between initial serum 25-hydroxyvitamin D (25(OH)D) levels with granulation growth in diabetic foot ulcers (DFUs) after 21 days of treatment. METHOD: This cohort study involved patients with type 2 diabetes who had a DFU treated at hospital. Blood samples were taken from patients on admission. The chemiluminescent immunoassay technique was used to measure 25(OH)D levels. Granulation tissue growth was analysed by comparing the photographs from the initial treatment to day 21 of treatment. RESULTS: The median value of 25(OH)D levels at initial treatment was 8 ng/ml. The result showed no correlation between 25(OH)D levels and the granulation growth in DFUs (p=0.86). CONCLUSION: The initial serum 25(OH)D level was not correlated with the growth of granulation tissue in DFUs.

Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-ß/Smad2/3.

Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-ß pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-ß1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1ß, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-ß1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-ß/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy.