Therapy For Diabetic Foot Ulcers Research Articles

Microenvironment-Based Diabetic Foot Ulcer Nanomedicine.

Diabetic foot ulcers (DFU), one of the most serious complications of diabetes, are essentially chronic, nonhealing wounds caused by diabetic neuropathy, vascular disease, and bacterial infection. Given its pathogenesis, the DFU microenvironment is rather complicated and characterized by hyperglycemia, ischemia, hypoxia, hyperinflammation, and persistent infection. However, the current clinical therapies for DFU are dissatisfactory, which drives researchers to turn attention to advanced nanotechnology to address DFU therapeutic bottlenecks. In the last decade, a large number of multifunctional nanosystems based on the microenvironment of DFU have been developed with positive effects in DFU therapy, forming a novel concept of "DFU nanomedicine". However, a systematic overview of DFU nanomedicine is still unavailable in the literature. This review summarizes the microenvironmental characteristics of DFU, presents the main progress of wound healing, and summaries the state-of-the-art therapeutic strategies for DFU. Furthermore, the main challenges and future perspectives in this field are discussed and prospected, aiming to fuel and foster the development of DFU nanomedicines successfully.

Renal Function Status in Patients with Diabetes Mellitus Having Diabetic Foot Infection and Role of Antibiotics

It has been shown that antibiotic therapy in diabetic foot ulcers has a toxic effect on renal function. Objective: To assess the renal function among patients with diabetes mellitus having diabetic foot infection. Methods: It was a cross-sectional retrospective study in the surgical Unit of DHQ Teaching Hospital KDA Kohat for six-month duration from January 2022 to June 2022. 130 patients with diabetic foot ulcers were selected for this study. The patients receiving antibiotic with a low renal toxicity risk were included in Group-A and patients receiving antibiotics with an increased renal toxicity risk were included in group B. GFR was calculated and measured from Cockcroft-Gault equation and serum creatinine levels. SPSS 20.0 was applied for data analysis with paired t-tests, t-test and chi-square tests. Results: In group A there were 65 (50%) participants and 65 (50%) in group B. GFR after and before antibiotic therapy was 58.30±31.13 cm3 / min and 65.98±35.76 cm3 / min (p = 0.004), correspondingly. The GFR in group B was reduced significantly after antibiotic therapy (p = 0.003). Conclusions: Conferring to this study, renal function decreased and nephrotoxicity was noted after antibiotic treatment, the percentage of decline in GFR being greater in patients who received higher nephrotoxic antibiotics.

The effectiveness of ozone therapy for diabetic foot treatment: A systematic review

Introduction: Diabetic foot ulcer is a local wound in patients with diabetes. Ozone therapy is becoming a treatment option as it accelerates healing. Objective: To verify the effectiveness of ozone therapy for the treatment of diabetic foot ulcers. Methodology: We performed searches in PubMed, SciELO, LILACS, MEDLINE, Web of Science and CINAHL databases until October 2021. The search included article references and clinical trial registry websites without limitation of language or publication date. Randomized and non-randomized clinical trials addressing ozone therapy in patients with diabetic foot ulcers were included. The Risk of Bias assessment tool and the Review Manager software, version 5.4 were used. Results: Six randomized and non-randomized clinical trials met the inclusion criteria (608 patients). Only two studies were considered to be at low risk of bias, with adequate randomization, allocation concealment, and blinded evaluation of results. One study compared two IPC regimens where there was evidence of a statistically significant treatment effect in favor of the rapid IPC regimen (hazard ratio 0.74, 95% CI 0.56 to 0.90). Five trials evaluated CPI as adjunctive therapy to standard therapies and agreed that CPI increases the rate of ulcer healing and a higher cure rate. Two trials evaluated CPI alone compared to other therapies. Conclusion: Ozone therapy for diabetic foot ulcers has been shown to be effective as an adjunct to standard treatment, although the included studies were classified as having a high risk of bias.

Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis.

To evaluate the efficacy and safety of topical oxygen therapy (TOT) in diabetic foot ulcers (DFUs), researchers systematically retrieved relevant studies from PubMed, EMBASE, Web of Science, CENTRAL and ClinicalTrials.gov. Relevant studies were searched from database inception to January 2022. Two researchers independently screened the literature, extracted data and assessed the quality of the included studies. Statistical analysis was performed in Stata 16.0. A total of seven RCTs involving 614 participants were included. Compared with the control group, the TOT group had a higher healing rate (RR=1.63, 95% CI [1.33, 2.00]). According to descriptive analysis, TOT reduced the ulcer area and improved healing durability and quality of life. Furthermore, it had no effect on the occurrence of adverse events. However, it was unclear whether it would be able to reduce the healing time. The existing evidence suggests that TOT is effective and safe for chronic DFUs. Further studies are warranted to validate our findings.

Xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells improves diabetic wound healing by promoting angiogenesis and lymphangiogenesis.

Some clinical trials have shown the usefulness of stem cell therapy for diabetic foot ulcers. However, the donor supply is limited, and the process is time consuming and expensive. This study assessed the therapeutic effects of neonatal porcine bone marrow-derived mesenchymal stem cell (npBM-MSC) xenotransplantation using diabetic wound model mice. All layers of back skin were removed from streptozotocin-induced diabetic mice. In the npBM-MSCs group, npBM-MSCs were transplanted to the wound, and syngeneic mouse bone marrow-derived mesenchymal stem cells (mBM-MSCs) were transplanted to the wound in the mBM-MSCs group. The control group comprised diabetic mice that did not receive cellular therapy. The therapeutic effects of the transplantation were evaluated according to the rate of wound closure and the promotion of neovascularization in the wound. The wound closure rate was significantly improved in the npBM-MSCs group compared with the control group (p<.001 at postoperative day [POD] 4 and p<.01 at POD 7) and mBM-MSCs groups (p<.05 at POD 4). Prominent promotion of both angiogenesis and lymphangiogenesis was observed in the npBM-MSCs group. Furthermore, the expression of murine Prox1 and both porcine and murine Vegfs and Tgfb1 in the wounds was enhanced until POD 4 by npBM-MSCs transplantation. The amounts of vascular endothelial growth factor (VEGF) A, VEGFC, and transforming growth factor β1 secreted from npBM-MSCs were higher than those from mBM-MSCs (p<.05). Xenotransplantation of npBM-MSCs improved diabetic wound healing by promoting both angiogenesis and lymphangiogenesis.

Stem Cell-Based Therapy for Diabetic Foot Ulcers.

Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.

Effectiveness of combined modulated ultrasound and electric current stimulation to treat diabetic foot ulcers.

The use of combined ultrasound and electrostimulation (CUSECS) as an adjunct therapy for diabetic foot ulcers (DFUs) is a relatively new concept. This study aimed to investigate if combined ultrasound and electrostimulation is an effective adjunctive treatment for hard-to-heal DFUs when compared with standard wound care. A randomised controlled pilot study design was used. Patients with hard-to-heal DFUs from two centres were sequentially randomised. For 8 weeks, the experimental group received CUSECS and standard wound care treatment twice a week. The control group received standard wound care treatment once a week. Wound changes were documented using photography, which also facilitated wound size measurement. Self-efficacy, economic cost, quality of life and reoccurrence rates were analysed as secondary objectives. The experimental group (n=6) achieved a higher rate of mean wound healing (mean difference (MD): 0.49) when compared to the control group (n=5, MD: 0.01). Two participants completed full healing in the experimental group and one in the control group. There were no statistically significant findings because of the small sample size. There were no direct adverse reactions to this therapy. Quality of life scores improved in the treatment group. There was no significant change in self-efficacy scores. Costs were higher in the experimental group; however, the healing rate was quicker, which could be extrapolated to cost reductions over time. Results suggest that CUSECS may be a useful adjunctive therapy for treatment of hard-to-heal DFUs. Further large-scale studies are needed to ascertain the effectiveness of CUSECS. The findings here are inconclusive but indicate that CUSECS may offer promise as a treatment.

Novel home use of mechanical negative pressure wound therapy in diabetic foot ulcers.

Mechanical negative pressure wound therapy is an ultraportable, light weight and disposable single-use device that has been shown to promote wound healing. This study evaluated home use of a mechanically powered negative pressure wound therapy (NPWT) in diabetic foot wounds. Patients underwent revascularisation and/or debridement or amputation before starting mechanical NPWT. Wound outcomes and images of the wounds were recorded at each follow-up visit by the wound nurse. Patients were followed up until wound closure or end of therapy. A total of 12 patients (each with one wound) were included in the study. Of the 12 wounds, 33.3% (n=4) of wounds achieved primary wound closure while the remaining 66.6% (n=8) of wounds demonstrated a mean wound size reduction of 37.5±0.13%. Of the closed wounds, mean time to healing was 4.75±2.50 weeks. There was 100% limb salvage with no further debridement or amputations, and no 30-day unplanned readmissions. Mean length of hospital stay before starting home NPWT was 9.75±6.31 days. Mean number of NPWT changes was 8.33±2.67 sessions, while mean duration of therapy was 4.0±1.54 weeks. Mean cost of home NWPT therapy was US$1904±731 per patient. The home use of mechanically powered NPWT in diabetic foot wounds demonstrated excellent wound healing rates and 100% limb salvage, with no complications.

The evaluation of efficacy of atmospheric pressure plasma in diabetic ulcers healing: A randomized clinical trial.

The aim of this study is to evaluate the efficacy and safety of cold atmospheric plasma (CAP) as a novel therapy for diabetic foot ulcers. This was an investigator-blinded, randomized controlled trial of 14 weeks (6 weeks of treatment and 8 weeks of follow-up). Twenty patients with diabetic foot ulcers were divided into two groups: the control group receiving standard wound care and the plasma group, which received CAP twice a week for six consecutive weeks in addition to standard wound care. The ulcer size, amount of exudate, and wound grading were determined weekly. Cold plasma was produced by applying a high voltage (4.5kV) and a high frequency (22 kHz) to helium gas. Exudate from wounds treated with CAP showed a significant reduction in the third week after complete treatment (p= 0.039). The wound grading of the ulcers improved by the sixth week (p= 0.019), and the sizes of ulcers significantly decreased in the plasma group at the end of the treatment period (p= 0.007). In this randomized clinical trial, CAP was an effective treatment option for diabetic foot ulcers in terms of wound surface reduction and antibacterial effects.

1031 A Mixed Methods Feasibility Study of Extracorporeal Shockwave Therapy for Diabetic Foot Ulcers

Abstract Aim The purpose of this mixed methods feasibility study was to assess the feasibility of delivering ESWT to patients with DFUs. It also aimed to explore any potential clinical effect of ESWT on wound healing and investigate whether ESWT may offer any patient reported benefits. Method A single centre mixed methods feasibility study. Patients with a DFU who met the eligibility criteria underwent ESWT 3 times in over 7 days. Primary outcome was feasibility of delivering the intervention. Secondary outcomes included wound size, number of DFU healed at 12 weeks and quality of life. Semi-structured interviews explored participants experience of undergoing ESWT. Results 22.6% (24/106) of patients screened were recruited. The mean attendance to clinic was 90.9% and 65.1% to follow up. The mean score for acceptability and tolerability was 9.86 (SD 0.48, 95% CI 9.62-10.01) and 9.15 (SD 2.57, 95% CI 7.87-10.42) respectively. There were no serious adverse events or side effects. 45.5% of DFU healed during follow up and quality of life scores improved until 8 weeks. Key themes identified from the qualitative interviews were desire for the fast healing, improved quality of life, new treatments must be flexible and accessible on transport. Conclusions This study has shown it is possible to recruit and retain patents into this research. This study supports development of a large randomised control trial to determine the clinical and cost effectiveness of ESWT for DFU healing.

A systematic review of ozone therapy for treating chronically refractory wounds and ulcers.

This study aims at evaluating the efficacy and safety of ozone therapy for chronic wounds. The Cochrane Library, PubMed, Ovid Embase, Web of Science, and Chinese Biomedical Literature Database were searched. Randomised controlled trials (RCTs) about participants with chronic wounds were included. Risk of bias assessment was performed by the Cochrane risk‐of‐bias tool. A randomised‐effects model was applied to pool results according to the types of wounds or ulcers. Among 12 included studies, ozone was implemented by topical application (ozone gas bath, ozonated oil, ozone water flushing) and systematic applications including autologous blood immunomodulation and rectal insufflation. The results indicated compared with standard control therapy for diabetic foot ulcers, ozone therapy regardless of monotherapy or combined control treatment markedly accelerated the improvement of the wound area(standardised mean difference(SMD) = 66.54%, 95% confidence interval (CI) = [46.18,86.90], P < .00001) and reduced the amputation rate (risk ration (RR) = 0.36, 95% CI = [0.24,0.54], P < .00001). But there is no improvement in the proportion of participants with completely healed wounds and length of hospital stay. No adverse events associated with ozone treatment have been reported. And the efficacy of ozone therapy for other wound types is still uncertain because of no sufficient studies. More high‐quality randomised controlled trials are needed to confirm the efficacy and safety of ozone therapy for chronic wounds or ulcers.

Proteomics changes after negative pressure wound therapy in diabetic foot ulcers.

Label-free quantitative mass spectrometry was used to analyze the differences in the granulation tissue protein expression profiles of patients with diabetic foot ulcers (DFUs) before and after negative-pressure wound therapy (NPWT) to understand how NPWT promotes the healing of diabetic foot wounds. A total of three patients with DFUs hospitalized for Wagner grade 3 were enrolled. The patients received NPWT for one week. The granulation tissue samples of the patients prior to and following NPWT for one week were collected. The protein expression profiles were analyzed with label-free quantitative mass spectrometry and the differentially expressed proteins (DEPs) in the DFU patients prior to and following NPWT for one week were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to annotate the DEPs and DEP-associated signaling pathways. Western blotting and ELISA were performed to validate the results. By comparing the differences in the protein profiles of granulation tissue samples prior to and following NPWT for one week, 36 proteins with significant differences were identified (P<0.05); 33 of these proteins were upregulated and three proteins were downregulated. NPWT altered proteins mainly associated with antioxidation and detoxification, the cytoskeleton, regulation of the inflammatory response, complement and coagulation cascades and lipid metabolism. The functional validation of the DEPs demonstrated that the levels of cathepsin S in peripheral blood and granulation tissue were significantly lower than those prior to NPWT (P<0.05), while the levels of protein S isoform 1, inter α-trypsin inhibitor heavy chain H4 and peroxiredoxin-2 in peripheral blood and granulation tissue were significantly higher than those prior to NPWT (P<0.05). The present study identified multiple novel proteins altered by NPWT and laid a foundation for further studies investigating the mechanism of action of NPWT.

Don’t delay wound-healing therapy for diabetic foot ulcers

Don’t delay wound-healing therapy for diabetic foot ulcers

A pharmacoeconomic study: cost-utility analysis of modern wound dressings vs conventional wound dressings in patients with diabetic foot ulcer

Introduction: Duration of treatment and outcome of therapy of diabetic foot ulcers are some of the factors that affect the quality of life and will require higher medical costs. Aim: This study aimed to choose an alternative wound dressing that provides the best utility at the most cost-efficient. Methods: The research method used was pharmacoeconomics with a patient’s perspective. Results: The results showed the mean cost of modern wound dressings per visit was IDR 347,131, while that of conventional wound dressings was IDR 47,140. The quality of life with modern vs conventional wound dressing was significantly different (p &lt; 0.05). The incremental cost utility ratio (ICUR) value was IDR 22,813 per quality of life (QoL). Conclusions: This study showed that modern wound dressings provide a higher quality of life at a higher cost. Indeed, it cost more than IDR 22,813 to change from conventional to modern wound dressings and increase 1 unit of quality of life, but patients obtained an additional 13.15 quality of life.

Stem cell transplantation therapy for diabetic foot ulcer: a narrative review.

Diabetes mellitus is a chronic metabolic disease associated with high cardiovascular risk. A vascular complication of diabetes is foot ulcers. Diabetic foot ulcers are prevalent and substantially reduce the quality of life of patients who have them. Currently, diabetic foot ulcer is a major problem for wound care specialists, and its treatment requires considerable health care resources. So far, various therapeutic modalities have been proposed to treat diabetic foot ulcers and one of them is stem cell-based therapy. Stem cell-based therapy has shown great promise for the treatment of diabetic foot ulcers. This strategy has been shown to be safe and effective in both preclinical and clinical trials. In this review, we provide an overview of the stem cell types and possible beneficial effects of stem cell transplantation therapy for diabetic foot ulcers, and an overview of the current status of stem cell research in both preclinical and clinical trial stages of treatment strategies for diabetic foot ulcers.

A case report: Treatment of chronic diabetic foot ulcer with Hyperbaric Oxygen Therapy

Diabetes mellitus effects around 10% of the whole population and unhealed diabetic foot ulcer is one of the most debilitating and economically burdensome conditions. This condition is commonly seen by different specialists including physicians, orthopaedic surgeons and vascular surgeons. We present a case of unhealed diabetic foot ulcer which has been treated in our Hyperbaric Oxygen Therapy (HBOT) centre. We also review the literature with respect to management strategy and rationale of hyperbaric oxygen therapy for diabetic foot ulcers.

Identification of potential circRNAs and circRNA-miRNA-mRNA regulatory network in the development of diabetic foot ulcers by integrated bioinformatics analysis.

We aimed to explore the mechanism of circular RNAs (circRNAs) and provide potential biomarkers for molecular therapy of diabetic foot ulcers (DFU). Gene expression profile of GSE114248, including five normal samples and five DFU samples, was downloaded from GEO database. Differentially expressed circRNAs (DEcircRNAs) between two groups were identified. Then, DEcircRNA‐miRNA and miRNA‐mRNA interaction was revealed, followed by the circRNA‐miRNA‐mRNA network construction. Moreover, functional and pathway analysis were performed based on mRNAs, followed by the DM‐related pathway exploration. Specific binding sites for key circRNAs and associated miRNAs were under investigation. Finally, RT‐qPCR was used to verify the candidate the relative expression level of circRNA between normal tissues and DFU. Totally, 65 DEcircRNAs were revealed between two groups, followed by 113 circRNA‐miRNA‐mRNA interactions explored. The mRNAs in these interactions were mainly assembled in functions like cell proliferation and pathways. Moreover, a total of 11 DM‐related pathways were revealed. Finally, circRNA‐miRNA specific binding‐site analysis revealed two key circRNAs, for example, circRNA_072697 and circRNA_405463, corresponding to their miRNAs. These two circRNAs were novel biomarkers for DFU. circRNA_072697 acted as a sponge of miR‐3150a‐3p in the progression of DFU via regulating KRAS. MAPK signaling pathway might contribute to the development of DFU.

Fluorescent angiography used as a tool to guide angiosome-directed endovascular therapy for diabetic foot ulcers

Angiosome-directed endovascular therapy for the treatment of chronic limb-threatening ischemia (CLTI) remains controversial owing to the overlap of wound angiosomes. Angiographic grading of success has limitations and translesional pressure assessments are seldom performed in the infrapopliteal vessels. Objective criteria to determine revascularization success in tibiopedal vessels have not been well described. Quantifying perfusion to a wound bed after establishing direct or indirect (via collateral) flow after revascularization is an important component for treating CLTI patients yet is seldom performed. We report the use of fluorescent angiography to quantitatively examine perfusion of a diabetic foot ulcer before and after angiosome-directed endovascular therapy.

Effectiveness and safety of human amnion/chorion membrane therapy for diabetic foot ulcers: An updated meta-analysis of randomized clinical trials.

Human amnion/chorion membrane therapy has shown advantages in the management of diabetic foot ulcers and its effectiveness has been evaluated in the systematic reviews and meta-analyses. However, the number of patients included in the previous literatures was small and the safety profile of human amnion/chorion membrane therapy was not concerned. Therefore, we conducted an updated meta-analysis to better understand the effectiveness and safety of human amnion/chorion membrane therapy for diabetic foot ulcers. The PubMed, Embase, Cochrane Library, and ClinicalTrial.gov databases were searched for any randomized clinical trials comparing human amnion/chorion membrane therapy and standard therapy in the treatment of diabetic foot ulcers. Ulcer healing rate was considered as the primary outcome and the secondary outcomes mainly included mean time to ulcer healing and adverse events. Nine RCTs with 541 patients were included. Compared with merely standard therapy, human amnion/chorion membrane therapy plus standard therapy improved the ulcer healing rates at 6 weeks (RR = 3.50, 95% CI: 2.35-5.21), 12 weeks (RR = 2.09, 95% CI: 1.53-2.85) and 16 weeks (RR = 1.70, 95% CI: 1.25-2.30), and also shortened the healing time (MD = -4.58, 95% CI: -5.70 to -3.46). Meanwhile, no significant difference was observed in the number of patients with adverse events (RR = 0.56, 95% CI: 0.31-1.03) between two groups. This meta-analysis suggests that human amnion/chorion membrane therapy as an adjuvant treatment could promote the healing of diabetic foot ulcers and has a safety profile. More evidence from large high-quality randomized clinical trials with long follow-up duration are in urgent need to further confirm our findings.

The Role of Recombinant Proteins and Growth Factors in the Management of Diabetic Foot Ulcers: A Systematic Review of Randomized Controlled Trials.

Background Recombinant proteins and growth factors are emerging therapies for diabetic foot ulcers. Despite several clinical reports, there has been no comprehensive and systematic assessment of the totality of clinical evidence on the efficacy and safety of recombinant proteins and growth factors in diabetic foot ulcers. We tried to address this gap through an updated systematic review of randomized controlled trials (RCTs). Methods PubMed, the Cochrane Library, Scopus, Embase, and Google Scholar databases were searched, and RCTs on the efficacy of recombinant proteins and growth factors in the treatment of cutaneous wounds in diabetic patients were selected. The literature search and assessment were performed by two independent reviewers. Methodological quality of studies was appraised using the Jadad scale. Results We identified 26 RCTs involving diabetic patients with ulcer that evaluated the effectiveness of platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, granulocyte colony-stimulating factor, vascular endothelial growth factor, erythropoietin, transforming growth factor, talactoferrin, and rusalatide acetate. The main primary outcome was complete healing though different indices were employed to define this such as wound closure, granulation tissue formation, or complete reepithelialization. Few studies had a follow-up period to report any recurrence and amputation rate. No adverse effect was reported due to the intervention. Conclusion Overall, there is a greater agreement on the effectiveness of EGF to enhance the healing of diabetic ulcers. Nevertheless, extant evidence is lacking for other agents since few trials have been conducted for most of the growth factors and available studies are heterogeneous in their methodologies.