Healing Of Diabetic Foot Ulcers Research Articles

Platelet lysate promotes the healing of long-standing diabetic foot ulcers: A report of two cases and in vitro study

Long-standing foot ulcers present a great challenge in diabetes care. Platelet products have been suggested as a possible therapeutic option. However, nor the effect of an injectable form of platelet lysate on the healing of ulcers nor that on primary cells of the epidermis have been studied. In the current study, we present two cases of an ongoing clinical trial showing the positive effect of autologous platelet lysate injected perilesional. Both clinical cases treated with injections of hPL showed complete healing of previously un-healed within 8 weeks of treatment. Further, we describe the in vitro effect of human platelet lysate (hPL) on primary human epidermal keratinocytes (HEK) in terms of chemotaxis, migration and proliferation. In vitro, HEK showed enhanced chemotaxis towards the hPL compared to keratinocyte-defined media (p < 0.0001). Their migration was also stimulated especially at hPL concentration of 10%V/V (p < 0.0001). In contrast, hPL significantly inhibited HEK proliferation measured through MTT assay (p < 0.0001). In conclusion, the findings presented here provide preliminary evidence of an explanatory mechanism for the effect of hPL on primary keratinocytes and therefore of their potential use in a clinical setting. hPL promotes keratinocyte migration and therefore closure of foot ulcers.

Comparison of a new versus standard removable offloading device in patients with neuropathic diabetic foot ulcers: a French national, multicentre, open-label randomized, controlled trial

IntroductionThe offloading is crucial to heal neuropathic diabetic foot ulcer (DFU). Removable offloading are the most used devices. Orthèse diabète is a new customized removable knee-high offloading device immobilizing foot...

Collagen/GAG scaffolds activated by RALA-siMMP-9 complexes with potential for improved diabetic foot ulcer healing.

Impaired wound healing of diabetic foot ulcers has been linked to high MMP-9 levels at the wound site. Strategies aimed at the simultaneous downregulation of the MMP-9 level in situ and the regeneration of impaired tissue are critical for improved diabetic foot ulcer (DFU) healing. To fulfil this aim, collagen/GAG (Col/GAG) scaffolds activated by MMP-9-targeting siRNA (siMMP-9) were developed in this study. The siMMP-9 complexes were successfully formed by mixing the RALA cell penetrating peptide with siMMP-9. The complexes formulated at N:P ratios of 6 to 15 had a diameter around 100nm and a positive zeta potential about 40mV, making them ideal for cellular uptake. In 2 dimensional (2D) culture of human fibroblasts, the cellular uptake of the complexes surpassed 60% and corresponded to a 60% reduction in MMP-9 gene expression in low glucose culture. In high glucose culture, which induces over-expression of MMP-9 and therefore serves as an in vitro model mimicking conditions in DFU, the MMP-9 gene could be downregulated by around 90%. In the 3D culture of fibroblasts, the siMMP-9 activated Col/GAG scaffolds displayed excellent cytocompatibility and ~60% and 40% MMP-9 gene downregulation in low and high glucose culture, respectively. When the siMMP-9 complexes were applied to THP-1 macrophages, the primary cell type producing MMP-9 in DFU, MMP-9 gene expression was significantly reduced by 70% and 50% for M0 and M1 subsets, in 2D culture. In the scaffolds, the MMP-9 gene and protein level of M1 macrophages decreased by around 50% and 30% respectively. Taken together, this study demonstrates that the RALA-siMMP-9 activated Col/GAG scaffolds possess high potential as a promising regenerative platform for improved DFU healing.

Validity of DMIST for monitoring healing of diabetic foot ulcers.

A new diabetic foot evaluation scale was proposed, using the seven domains of depth, maceration, inflammation/infection, size, tissue type of the wound bed, type of wound edge, and tunneling/undermining. This scale was named "DMIST" as an acronym from the initials of the domains. The purpose of this study was to evaluate the validity of DMIST. Secondary analysis was conducted in three investigations performed using the diabetic foot ulcer assessment scale (DFUAS) in Japan and Indonesia. Secondary analysis was assessed using DMIST, PUSH, and DESIGN for 4 weeks based on DFUAS score and photographs of diabetic foot ulcers by researchers. Concurrent validity was determined from the correlation of total DMIST scores with PUSH and DESIGN scores. Construct validity was determined by comparisons between total DMIST score and grade of the Wagner classification. Predictive validity was determined by receiver operating characteristic curve analysis for wound non-healing 4 weeks later. Subjects comprised 35 Japanese patients and 118 Indonesian patients. Correlations of total DMIST score with PUSH and DESIGN scores were 0.831 and 0.822, respectively. Comparison of total DMIST scores with grade of the Wagner classification (Grade I vs. Grade II/III vs. Grade IV/V) was p < 0.001. Based on an area under the curve of 0.872, a DMIST score of 9 was selected as a cut-off, offering sensitivity of 0.855 and specificity of 0.786 for wound non-healing 4 weeks later. Our findings suggest that DMIST offers high validity.

Maggot excretions/secretions promote diabetic wound angiogenesis via miR18a/19a – TSP-1 axis

AimsThe impaired angiogenesis is one of the main factors affecting the healing of diabetic foot ulcer (DFU) wounds. Maggot debridement therapy (MDT) promotes granulation tissue growth and angiogenesis during DFU wound healing. Non-coding microRNAs can also promote local angiogenesis in DFU wounds by regulating wound repairing related gene expression. The purpose of this study was to investigate the mechanism of microRNAs in MDT promoting DFU wound angiogenesis. MethodsIn this study, we applied MDT to treat DFU wound tissue and detect the expression of the miR-17–92 cluster. In vitro experiments, human umbilical vein endothelial cells (HUVECs) were treated with maggot excretions/secretions (ES), the miR-17–92 cluster and the predicted target gene expression were measured. Tube formation assay and cell scratch assay were performed when inhibition of miR-18a/19a or overexpression of thrombospondin-1 (TSP-1) were used in this study. ResultsmiR-18a/19a transcription significantly up-regulated and TSP-1 expression down-regulated in patients wound tissue and in HUVECs. Inhibition of miR-18a/19a or overexpression of TSP-1 partially blocked the migration and tube formation ability stimulated by ES. ConclusionTargeted activation of miR-18a/19a transcription levels and subsequent regulation of TSP-1 expression may be a novel therapeutic strategy for DFU.

A COMPARATIVE STUDY OF TOPICAL INSULIN AND NORMAL SALINE DRESSING IN WOUND HEALING IN DIABETIC FOOT ULCER

Background: Diabetes mellitus is multifactorial multiorgan disease characterized by state of hyperglycemia in the body. The present study was conducted to compare topical insulin and normal saline dressing in wound healing in diabetic foot ulcer. Materials & Methods: The present study was conducted on 108 diabetic patients with diabetic foot ulcer of both genders. Patients were randomly classified into 2 groups. Each group comprised of 54 patients. Group I patients were treated with topical insulin dressings and group II patients were treated with normal saline dressings. Size of the ulcer was measured at the beginning and on regular interval after 7 days and 14 days. Mean depth and presence of slough was also recorded. Results: The mean size of the ulcer was 5.4 cm2 in group I and 5.2 cm2 in group II and depth of the ulcer was 8.2 mm in group I and 8.0 mm in group II. All 54 patients had slough in both groups and none had granulation tissue in both groups at day 0. The difference was non- significant (P> 0.05). The mean size of the ulcer was 3.8 cm2 in group I and 4.5 cm2 in group II and depth of the ulcer was 6.8 mm in group I and 7.8 mm in group II. 14 patients in group I and 28 in group II had slough and 40 patients in group I and 26 in group II had granulation tissue at day 7. The mean size of the ulcer was 1.8 cm2 in group I and 2.9 cm2 in group II and depth of the ulcer was 3.4 mm in group I and 4.8 mm in group II. 5 patients in group I and 20 patients in group II had had slough and 49 patients in group I and 34 in group II had granulation tissue at day 14. The difference was significant (P< 0.05). Conclusion: Authors found that topical insulin is efficient in patients with diabetic foot ulcer as compared to normal saline. There was fastest recovery and reduction in size of ulcer with insulin.

Abstract 187: Human Cryopreserved Skin Allografts Recruit M2-macrophages And Induce Angiogenesis In A Murine Xenograft Model

Purpose: For over 50 years, human cryopreserved skin allografts (HCAs) have been used for temporary coverage of major burns when autograft donor sites are insufficient. HCAs have also been shown to promote healing of diabetic foot ulcers and prevent fluid loss and infections. Their mechanism of action, however, remains elusive. Methods: HCA and human acellular dermal matrix (ADM) grafts were implanted subcutaneously in C57BL/6 (WT) mice and explanted after 1, 3, 7, 14, and 28 days (n= 5 per group). A sham surgery served as a control. Immunofluorescent staining (IF) of tissue sections was used to determine the immune reaction against HCA and ADM as well as vascularization and pro-angiogenic signaling within the grafts and the overlaying mouse skin. HCA and ADM grafts were also implanted into WT mice parabiosed to GFP-positive mice to analyze the infiltration of circulating cells by IF and flow cytometry. HCA grafts explanted after 14 days were processed for droplet-based microfluidic single cell RNA sequencing (scRNA seq) of infiltrating cells using the 10X Genomics platform. Data were log-normalized and partitioned using UMAP based density mappings. Results: Subcutaneous pockets with implanted grafts healed without clinically apparent rejection. Immune cell infiltration, characterized by F4/80, CD11c, and Myeloperoxidase staining, was greater in HCA compared to ADM on post-implantation day 3, whereas no differences were seen on day 7. CD31 staining showed significantly greater vascularization in HCA on day 7 compared to ADM and sham. HCA also demonstrated higher VEGF expression. A greater number of circulating GFP+ cells were found in HCA compared to ADM and sham by IF and FACS. scRNA seq identified 11 distinct cell clusters out of which 2 were defined as macrophage sub-populations, which highly expressed classical M2 macrophage genes (Mrc1, Arg1, Retnla, Cd163). One M2 subpopulation also highly expressed Col3a1 and pro-angiogenic Hif1a. Conclusion: Our data indicate that the immune reaction to HCA is associated with macrophage polarization towards an M2 phenotype. We have identified a sub-population of pro-angiogenic, collagen-3 expressing macrophages, which may be responsible for increased vascularization after HCA implantation in our xenograft model and may underlie the beneficial clinical effects of HCA transplantation.

Intralesional epidermal growth factor application is a potential therapeutic strategy to improve diabetic foot ulcer healing and prevent amputation.

This study aimed to investigate the efficacy of intralesional epidermal growth factor (EGF) in preventing the extremity from a major amputation and its effects on wound healing in chronic diabetic foot ulcers (DFUs). Thirty-three patients with DFUs were treated with intralesional EGF application between January 2013 and January 2017. The first endpoint was to determine the prevention rate of major amputation within 12 months following treatment. The second endpoints were the recovery of ulcer surface area with ≥ 50% granulation following two months and the healing of ulcer surface area with ≥ 75% granulation following six months after the first application of EGF. After three patients were excluded because of major side effects in the remaining 30 patients (48 DFUs), granulation rate of ≥ 50% was achieved in 24 (37 DFUs) patients, and not achieved in 6 (11 DFUs) patients eight weeks following the EGF application. A granulation rate of ≥ 75% was achieved in 21 (31 DFUs) patients after six months. At 12 months following the treatment, one major and seven minor amputations were performed, a total of 10 DFUs in five patients were not healed, and the DFUs in 17 patients completely recovered. Intralesional EGF application has positive results in addition to good foot care in DFUs, and promising results can be obtained by protecting the extremity from amputation by using it in patients whose vascular intervention methods are not appropriate and have DFUs that do not heal with conventional wound care treatments.

Cyclical pressurized topical wound oxygen therapy increased healing of refractory diabetic foot ulcers.

Source Citation Frykberg RG, Franks PJ, Edmonds M, et al. A multinational, multicenter, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxyge...

Comparison of honey and natural ointment based on honey-tea tree oil on the healing of diabetic foot ulcer

This study aimed to compare the impact of honey and natural ointment based on honey-Tea Tree Oil. This was a quasi-experimental study with a pre-post control group design approach. The sample consisted of 27 respondents in two different wound care clinics. The instruments used were the Leg Ulcer Measurement Tool (LUMT) measured on day 1, 7 and 14. Data was analyzed using paired t-test, pooled t-test, and multiple regression test. Most participants were female, the average age was 50.89 years, the average duration of illness for type II diabetes was 3.56 and had current infection. The results showed a significant difference in LUMT score between before and after treatment of wounds healing in the two intervention groups (p-value=0.000). Honey and natural ointment based on honey - tea tree oil significantly contributed to the healing of Diabetic Foot Ulcer.

Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review.

The management of diabetic foot ulcers (DFU) remains a challenge, and there is continuing uncertainty concerning optimal approaches to wound healing. The International Working Group of the Diabetic Foot (IWGDF) working group on wound healing has previously published systematic reviews of the evidence in 2008, 2012 and 2016 to inform protocols for routine care and to highlight areas which should be considered for further study. The working group has now updated this review by considering papers on the interventions to improve the healing of DFU's published between June 2014 and August 2018. Methodological quality of selected studies was independently assessed by a minimum of two reviewers using the recently published 21-point questionnaire as recommended by IWGDF/European Wound Management Association, as well as the previously incorporated Scottish Intercollegiate Guidelines Network criteria. Of the 2275 papers identified, 97 were finally selected for grading following full text review. Overall, there has been an improvement in study design and a significant rise in the number of published studies. While previous systematic reviews did not find any evidence to justify the use of newer therapies, except for negative pressure wound therapy in post-surgical wounds, in this review we found additional evidence to support some interventions including a sucrose-octasulfate dressing, the combined leucocyte, fibrin and platelet patch as well as topical application of some placental membrane products, all when used in addition to usual best care. Nonetheless, the assessment and comparison of published trials remains difficult with marked clinical heterogeneity between studies: in patient selection, study duration, standard of usual care provision and the timing and description of the clinical endpoints.

Pilot study of the safety and efficacy of angiogenic therapy in diabetic foot syndrome

BACKGROUND: The syndrome of diabetic foot remains the main cause of non-traumatic amputation of the lower extremity in the world. Even with the provision of comprehensive medical care in the conditions of a specialized center, 10-15% of patients do not succeed in healing the ulcerative defect due to the ischemic component.&#x0D; AIMS: The objective of this study is evaluation of safety and efficacy of pl-VEGF165 transfer in patients with neuroischemic type of diabetic foot syndrome.&#x0D; METHODS: The pilot study included 35 diabetic patients with neuroischemic foot ulcers (Wagner stage 1-2) who were not candidates for revascularization procedures (NCT02538705). The patients were closely monitored after repeated pl-VEGF165 intramuscular gene transfer (2,4 mg) at 1, 3, and 6 months after treatment. The primary efficacy endpoint was the surface area of the ulcers (sq.cm), the secondary endpoints were transcutaneous oxygen tension (Tcp02), ankle-brachial index (ABI), neuropathy disability score (NDS), neuropathy symptoms score (NSS), and Michigan neuropathy screening instrument (MNSI). Adverse events were monitored throughout the study.&#x0D; RESULTS: The use of pl-VEGF165 as part of complex treatment allowed to achieve wound healing in 65,7% of patients with chronic ulcerative defects, the safety of the target limb was 84%. Carrying out therapeutic angiogenesis as a part of the combined therapy ensured a reduction in the average area of the resistant to treatment defects from 3.6 [1.0; 7.05] cm2 to 0.0 [0.0;2.0] cm2 (p=0,001), which correlated with an increase in the TcPo2 index by 15% from 35 [29.5; 40.5] to 40.5 [36.0; 46.5] mm Hg (p= p=0,005) and in the ABI by 16% from 0.96 [0.82;1.08] to 1.11 [0.85; 1.24] (p=0,062). The decrease in the signs of diabetic neuropathy was determined - the scores of NSS scales and VAT decreased from 6,5 [5.75; 8.0) to 6.0 [5.25; 7.0] (p=0,004) and from 9.0 [8.0; 13.5] to 8.0 [7.0; 12.7] (p=0,001), respectively. No adverse effects associated with the use of pl-VEGF165 were recorded.&#x0D; CONCLUSIONS: Thus, preliminary results of the pilot study show that the use of pl-VEGF165 gene transfer in combination therapy allows for complete healing of neuroischemic diabetic foot ulcers in the majority of patients.

Operative Intervention Does Not Change Pain Perception in Patients With Diabetic Foot Ulcers.

Researchers investigated pain perception in patients with diabetic foot ulcers (DFUs) by analyzing pre- and postoperative physical function (PF), pain interference (PI), and depression domains of the Patient-Reported Outcome Measurement Information System (PROMIS). They hypothesized that 1) because of painful diabetic peripheral neuropathy (DPN), a majority of patients with DFUs would have high PROMIS PI scores unchanged by operative intervention, and 2) the initially assessed PI, PF, and depression levels would be correlated with final outcomes. Seventy-five percent of patients with DFUs reported pain, most likely because of painful DPN. Those who reported high PI and low PF were likely to report depression. PF, PI, and depression levels were unchanged after operative intervention or healing of DFUs.

Evaluation of Efficacy of Pulsed Electromagnetic Field Therapy as an Adjuvant Therapy in Healing of Diabetic Foot Ulcers

Background and Aim: Foot ulcer is a common complication of diabetes mellitus. The life time risk ofdeveloping foot ulcer is 25 % with an annual incidence of 2-3% and may result in limb amputation if leftuntreated. Diabetic foot ulcers are conventionally treated with wound debridement and off loading. Properwound healing is uncertain in conservative management of these ulcers. Pulsed Electromagnetic Fieldtherapy is a new modality that interacts at various steps in wound healing. This study aims at evaluating theefficacy of pulsed electromagnetic field therapy as an adjunct therapy in diabetic foot ulcers. Method andmaterials: Thirty patients with mean duration of Diabetes 7.8 ±1.47 yrs, mean duration of foot ulcer 4.9±1.2months with Wagner’s grade 1 and 2 were subjected to Pulsed electromagnetic field for 45 min/day for 30days Statistical Analysis: Data was analysed using student paired t -test Results: The patients showed overall66% ±15% reduction in the wound surface area. Less than 50 % reduction is reported in 2 of the patients.About 50-59% reduction is noted in 6 patients, 11 patients showed 60-69% reduction, 7 patients showed 70-79% reduction, 2 patients more than 90% reduction and 2 patients showed 80-89% reduction in the woundarea. None of them reported any side effects. P value of &lt;0.05 was taken to be significant. Discussion andconclusion: Significant reduction in wound surface area observed could be due to Pulsed ElectromagneticField therapy that helped in healing of tissues, improved circulation and reduced inflammation. Thus PEMFcan be an effective and safe adjuvant therapy for treating diabetic foot ulcers.

Wheeling to Healing: A Novel Method for Improving Healing of Diabetic Foot Ulceration

Wheeling to Healing: A Novel Method for Improving Healing of Diabetic Foot Ulceration

A Narrative Review of the Use of Neuromuscular Electrical Stimulation in Individuals With Diabetic Foot Ulceration.

This review aims to summarize the evidence reported on the use of neuromuscular electrical stimulation (NMES) in individuals with diabetic foot ulceration (DFU). A systematic search of EMBASE and MEDLINE databases was performed in February 2019, using search terms relating to the domains DFU and NMES. All primary evidence assessing outcomes of NMES in DFU were included. Of 344 references obtained from database searching, 7 met the inclusion criteria and included a total of 140 participants, 77 of whom had DFU. All included studies used prospective designs. Two studies demonstrated improvements in chronic ulcer healing with NMES use; however, in each study, only 3 of the included participants had DFU and subgroup analyses based on ulcer etiology was omitted. The remaining 5 studies were produced by the same research group and positive effects of NMES (in combination with heat therapy) on DFU healing were consistently demonstrated. They reported significantly better healing rates with NMES in DFU than in nondiabetic wounds of a similar grade (healing rate: 70.0 ± 32.3% in DFU vs 38.4 ± 22.3% in nondiabetic ulcers [P < .01]). These studies did not provide data assessing the isolated effects of NMES without concomitant heat exposure. Data on device tolerability and compliance were lacking. The existing data support a potential role for NMES in individuals with DFU; however, the identified studies inadequately controlled for confounding and were underpowered. Given the significant morbidity and mortality associated with DFU, higher quality evidence is needed to assess the adjunctive role for NMES in this group.

Major Improvement in Wound Healing Through Pharmacologic Mobilization of Stem Cells in Severely Diabetic Rats.

Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow-derived CD133+ and CD34+ endothelial progenitor cells and Ym1/2+ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.

CORR Insights®: Proximal Tibial Cortex Transverse Distraction Facilitating Healing and Limb Salvage in Severe and Recalcitrant Diabetic Foot Ulcers.

CORR Insights®: Proximal Tibial Cortex Transverse Distraction Facilitating Healing and Limb Salvage in Severe and Recalcitrant Diabetic Foot Ulcers.

Comparison of octenidine wound gel versus povidone-iodine dressing in healing of chronic diabetic foot ulcers: A randomized controlled trial for period of 1 year

Context: Octenidine is an antiseptic known for the past 20 years. Very few clinical studies have been done in evaluating the advantages of octenidine. Specific characters of no anti microbial resistance, good host tissue tolerability and very few clinical studies made us to conduct this study. Aims: To compare octenidine wound gel dressing versus povidone-iodine (PVI) dressing in healing of chronic diabetic foot ulcers (DFUs) in terms of mean percentage reduction in the ulcer area. Settings and Design: A randomized controlled study was conducted at a tertiary care hospital in North Karnataka between January 2018 and December 2018. Subjects and Methods: Eighty cases of chronic DFU were selected and randomized (sequentially numbered, opaque-sealed envelopes technique) into two groups – Group A: octenidine dressing done and Group B: PVI dressing done for 14 days. The wound healing was calculated as the mean percentage reduction in the ulcer area. The wound healing was then compared between two groups. Statistical Analysis Used: Student's unpaired t-test and Chi-square test were used for analysis. Results: Ulcer healing was early in Group A compared to Group B; the mean percentage reduction in the ulcer area was 25.51 ± 9.26 and 14.48 ± 6.54 sq.cm in Group A and Group B, respectively (P Conclusions: Octenidine wound gel has shown good progress of ulcer healing in terms of ulcer area reduction compared to PVI dressing.

Does intensive glycaemic control promote healing in diabetic foot ulcers? – a feasibility study

IntroductionOne in four diabetes patients will develop a foot ulcer over their lifetime. The role of glycaemic control in the healing of foot ulcers in diabetes patients is not supported...