Chronic Diabetic Foot Ulcers Research Articles

Transcriptomics Revealed Differentially Expressed Transcription Factors and MicroRNAs in Human Diabetic Foot Ulcers

Non-healing diabetic foot ulcers (DFUs) not only significantly increase morbidity and mortality but also cost a lot and drain healthcare resources. Persistent inflammation, decreased angiogenesis, and altered extracellular matrix remodeling contribute to delayed healing or non-healing. Recent studies suggest an increasing trend of DFUs in diabetes patients, and non-healing DFYs increase the incidence of amputation. Despite the current treatment with offloading, dressing, antibiotics use, and oxygen therapy, the risk of amputation persists. Thus, there is a need to understand the molecular and cellular factors regulating healing in DFUs. The ongoing research based on proteomics and transcriptomics has predicted multiple potential targets, but there is no definitive therapy to enhance healing in chronic DFUs. Increased or decreased expression of various proteins encoded by genes, whose expression transcriptionally and post-transcriptionally is regulated by transcription factors (TFs) and microRNAs (miRs), regulates DFU healing. For this study, RNA sequencing was conducted on 20 DFU samples of ulcer tissue and non-ulcerated nearby healthy tissues. The IPA analysis revealed various activated and inhibited transcription factors and microRNAs. Further network analysis revealed interactions between the TFs and miRs and the molecular targets of these TFs and miRs. The analysis revealed 30 differentially expressed transcription factors (21 activated and 9 inhibited), two translational regulators (RPSA and EIF4G2), and seven miRs, including mir-486, mir-324, mir-23, mir-186, mir-210, mir-199, and mir-338 in upstream regulators (p < 0.05), while causal network analysis (p < 0.05) revealed 28 differentially expressed TFs (19 activated and 9 inhibited), two translational regulators (RPSA and EIF4G2), and five miRs including mir-155, mir-486, mir-324, mir-210, and mir-1225. The protein–protein interaction analysis revealed the interaction of various novel proteins with the proteins involved in regulating DFU pathogenesis and healing. The results of this study highlight many activated and inhibited novel TFs and miRs not reported in the literature so far, as well as the targeted molecules. Since proteins are the functional units during biological processes, alteration of gene expression may result in different proteoforms and protein species, making the wound microenvironment a complex protein interaction (proteome complexity). Thus, investigating the effects of these TFs and miRs on protein expression using proteomics and combining these results with transcriptomics will help advance research on DFU healing and delineate potential therapeutic strategies.

Molecular Detection of Beta-Lactamase Genes (KPC and CTX-M) of Pseudomonas aeruginosa in Diabetic Foot Ulcers Patients

Background: diabetic foot ulcers (DFUs ) are an inflammatory disease caused by a bacterial infection such as Pseudomonas aeruginosa (P. aeruginosa), provided with genetic virulence factors. This study aims to detect KPC and CTX-M genes of P. aeruginosa isolated from chronic DFU patients. Methods: One hundred twenty DFU patients were recruited from Al-Sader Medical City and Al-Hakim General Hospital in Najaf province from September to January 2021 to collect ear swaps. The Primary identification depends on Gram stain and biochemical tests. We also used the Vitek 2 system to make another identification and examine resistance to antibiotics. A polymerase chain reaction (PCR) was used to amplify the required genes. Furthermore, gel electrophoresis was performed to show the amplified genes. Results: The results have revealed that 100 samples (83.3%) give a positive outcome, while 20 samples (16.6%)are negative for culture bacteria. Only 17(17 %) of the 100 clinical specimens showed positive tests for P. aeruginosa. However, the gene, CTX-M gene is found in 58.8% of P. aeruginosa isolates, while the KPC gene is not found in the isolates. Conclusion: Our findings suggest that P. aeruginosa is one of the most common causes of DFU infection in Iraqi patients and The levels of MDR of P. aeruginosa isolates in Najaf hospitals were undoubtedly high. Most bacterial isolates show the presence of the CTX-M gene. The presence of these genes is one of the virulence factors and probably partly explains the resistance to antibiotics.

A comparative analysis of vacuum assisted closure therapy and conventional dressings: outcomes in chronic diabetic foot ulcers among Indian patients

Background: India faces a growing diabetes epidemic, with approximately 77 million individuals affected. Chronic non-healing diabetic foot ulcers (DFUs) are a common complication of diabetes and a major healthcare challenge in Conventional wound care methods often result in prolonged healing times, increasing the risk of infection, hospitalization, and amputations. Vacuum-assisted closure (VAC) therapy, a modern treatment modality, offers a potentially more effective approach to managing these ulcers. Methods: This prospective, observational study was conducted at a tertiary care hospital in India from March 2022 to March 2024. One hundred patients with chronic non-healing DFUs were randomized into VAC therapy or conventional dressing groups. The primary outcomes included wound size reduction and healing time, while secondary outcomes involved patient satisfaction and cost-effectiveness. Results: VAC therapy significantly reduced wound size (65.2% vs. 40.5%) and shortened healing time (6.2 vs. 10.9 weeks) compared to conventional dressings. Additionally, VAC therapy led to higher patient satisfaction and proved more cost-effective due to fewer dressing changes and shorter hospital stays. Conclusions: VAC therapy outperforms conventional dressings in managing DFUs, offering faster healing, better patient satisfaction, and cost-effectiveness. Expanding its use in India could greatly improve diabetic foot care outcomes.

Retention processed placental membrane versus standard of care in treating diabetic foot ulcers.

Diabetic foot ulcers (DFUs) are a severe complication for diabetic patients, significantly impacting patient quality of life and healthcare system efficiency. Traditional standard of care (SOC) treatments are inadequate for many patients, necessitating the use of advanced wound care products, such as human placental membranes. We studied a real-world population of large, hard-to-heal and complicated wounds, otherwise under-studied in the wound care literature. To this end, we conducted a retrospective cohort analysis to compare the effectiveness of a human placental amnion/chorion membrane product using retention-based processing (RE-AC) and SOC in managing chronic DFUs. During the study period of September 2021 through April 2024, we collected retrospective observational data from electronic health records of 21 patients treated with RE-AC at three outpatient wound care centres. Additionally, 21 control SOC patients were matched from a wound registry using Coarsened Exact Matching. Patients were categorized into two cohorts based on whether they received RE-AC or SOC. Key metrics included wound size progression and wound closure. The analysis employed Bayesian regression and Hurdle Gamma Analysis of Covariance models. Despite their rather large size (average of 13.8 cm2), our results indicated that RE-AC achieved almost a 10% higher expected wound closure rate compared to SOC at 12 weeks (8.53% [credible interval: 5.60%-10.7%]). Further, for wounds that did not close, RE-AC resulted in a 93.6% (credible interval: 147.7%-41.6) improvement in expected Percent Area Reduction over the SOC group at 12 weeks. We noted that on average, SOC wounds stalled or grew larger. In terms of a risk ratio comparing the study group with SOC, we found a 52% benefit in the RE-AC group (RR = 1.52). The findings suggest that even with larger DFUs, R-AC is superior to SOC for wound closure and expected Percent Area Reduction by 12 weeks. This benefit likely leads to reduced treatment costs, optimized resource utilization and improved outcomes in the DFU patient population; ultimately resulting in improved patient care.

A multicentre clinical trial evaluating the outcomes of two application regimens of a unique keratin-based graft in the treatment of Wagner grade one non-healing diabetic foot ulcers.

Diabetic foot complications that lead to lower extremity amputations pose a significant challenge to the entire global health system. In this multicentre clinical trial, 26 patients with chronic Wagner one diabetic foot ulcers (DFUs) were treated with a unique human keratin matrix graft applied either weekly or bi-weekly, in addition to standard of care. The hypothesis was that bi-weekly application would be similar to weekly application. The primary endpoint was complete wound closure by 12 weeks, and secondary endpoints included healing time, percent area reduction and weekly changes in peripheral neuropathy, pain and quality of life. In the intent-to-treat population, 77% (10/13) of DFUs treated with bi-weekly application healed compared with 69% (9/13) treated with weekly application. The mean time to heal within 12 weeks in the bi-weekly group was 61 days and in the weekly group was 54 days. The mean percent area reduction at 12 weeks was 94.7% in the bi-weekly group compared with 84.8% in the weekly group. The number of grafts used in the bi-weekly group was 3.9 compared with 6.2 in the weekly group. The results of this trial confirm our hypothesis that whether bi-weekly or weekly application of the unique keratin matrix graft is used to treat nonhealing indolent DFUs, there is a high rate of complete healing. Based on these results, future studies should be conducted that further investigate the use of this novel human keratin matrix graft for the treatment of chronic DFUs.

Novel Factors Regulating Proliferation, Migration, and Differentiation of Fibroblasts, Keratinocytes, and Vascular Smooth Muscle Cells during Wound Healing.

Chronic diabetic foot ulcers (DFUs) are a significant complication of diabetes mellitus, often leading to amputation, increased morbidity, and a substantial financial burden. Even with the advancements in the treatment of DFU, the risk of amputation still exists, and this occurs due to the presence of gangrene and osteomyelitis. Nonhealing in a chronic DFU is due to decreased angiogenesis, granulation tissue formation, and extracellular matrix remodeling in the presence of persistent inflammation. During wound healing, the proliferation and migration of fibroblasts, smooth muscle cells, and keratinocytes play a critical role in extracellular matrix (ECM) remodeling, angiogenesis, and epithelialization. The molecular factors regulating the migration, proliferation, and differentiation of these cells are scarcely discussed in the literature. The literature review identifies the key factors influencing the proliferation, migration, and differentiation of fibroblasts, keratinocytes, and vascular smooth muscle cells (VSMCs), which are critical in wound healing. This is followed by a discussion on the various novel factors regulating the migration, proliferation, and differentiation of these cells but not in the context of wound healing; however, they may play a role. Using a network analysis, we examined the interactions between various factors, and the findings suggest that the novel factors identified may play a significant role in promoting angiogenesis, granulation tissue formation, and extracellular matrix remodeling during wound healing or DFU healing. However, these interactions warrant further investigation to establish their role alone or synergistically.

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.

Patient with Diabetic Foot Ulcer Admitted in Surgery Ward; Risk Factors, Associations and Grades of Presentation

Background: The management of chronic diabetic foot ulcers (DFU) poses a great challenge to the treating physician and surgeon. The aim of this study was to identify the risk factors, clinical presentation, and outcomes associated with chronic DFU. Objective: To determine the various risk factors for diabetic foot ulcers and study their associations. To study the grades of diabetic foot ulcers at presentation. Method: Purposive sampling. This study was done in the Surgery department of Shaheed Ziaur Rahman Medical College Hospital (SZMCH), Bogura for period of twelve (12) months. 100 cases were selected after informed consent. Study group (A) comprises of 50 cases of type 2 diabetes with diabetic foot ulcer and control group (B) comprises of 50 cases of age and gender matched type 2 diabetics without foot ulcers. Patients having serious systemic illness, type I diabetics and non-diabetic patients presenting with foot ulcer were excluded. Age, gender, duration of diabetes, duration of ulcer, glycemic control, presence of neuropathy and vascular disease were documented. Grading and Staging of ulcer was done according to New University of Texas Diabetic Wound Classification. Various risk factors were compared between the two groups. Data analyzed via SPSS version 17 with significant p-value < 0.05. Results: Among 100 cases (64 % males & 36 % females); mean age was 58.50 ± 9.8 (group A) versus 50.40 ± 10.5 (group B). Mean duration of diabetes was longer in group A (10.49 ± 7.06 years) vs. group B (8.34 ± 4.83 years) (p = 0.019). Glycemic control was poor in group A (72 %) vs. group B (56 %) (p = 0.045). There was significantly more peripheral vascular disease in group A (50 %) vs. group B (32 %) (p= 0.005). Sensory neuropathy was more in group A (90 %) vs. group B (38 %) (p < 0.0001). Grade-I ulcer was present in 16 % cases, Grade-II in 38 % and Grade-III in 46 %. Conclusion: Neuropathy carries highest risk for diabetic foot ulcer, followed by peripheral vascular disease and poor glycemic control. Therefore, diabetic patient must be educated about these risk factors, foot care and self-examination and to have regular screening by clinician. Appropriate glycemic control and timely medical and surgical intervention may reduce morbidity in diabetics.

Results of the Phase 1 Open-Label Safety Study of Umbilical Cord Lining Mesenchymal Stromal/Stem Cells (Corlicyte®) to Heal Chronic Diabetic Foot Ulcers.

Mesenchymal stromal/stem cells (MSCs) play a critical role in wound healing. Corlicyte® is an MSC product derived from allogeneic umbilical cord tissue donated under an institutional review board-approved protocol and processed in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. This open-label phase 1 trial was performed under a United States Food and Drug Administration Investigational New Drug Application to establish the safety and tolerability of Corlicyte® in patients with diabetes and chronic diabetic foot ulcer (DFU). Escalating doses were applied topically twice a week for up to 8 weeks after ulcer debridement, wound photography, and measurement. Subjects were followed for 4 weeks after the treatment phase. Adverse events were assessed at every visit. Nine subjects in 2 dosing cohorts completed the trial. No subjects experienced a serious adverse reaction to Corlicyte® or the development of anti-human leukocyte antigen (HLA) antibodies. Sixty percentage of subjects in the lower dose cohort experienced ulcer closure by Day 70 of follow-up, while the mean ulcer size was reduced by 54-67% in the other subjects. Topical administration of Corlicyte®, a novel biologic therapy consisting of allogeneic umbilical cord lining MSCs, appeared safe and tolerable and resulted in a significant decrease in ulcer area, demonstrating its potential as a therapy for healing of chronic DFU.

A randomized, placebo-controlled study of chitosan gel for the treatment of chronic diabetic foot ulcers (the CHITOWOUND study)

IntroductionTo assess the efficacy of a chitosan-based gel (ChitoCare) for the treatment of non-healing diabetic foot ulcers (DFUs).Research design and methodsForty-two patients with chronic DFUs were randomized to the ChitoCare...

Biofriendly resveratrol loaded glycerosomal nanovesicles improve wound healing in chronic diabetic foot ulcers: In-vitro &in-vivo efficacy evaluation

Chronic diabetic foot ulcers (CDFUs) are complex pathological processes involving persistent inflammation, significantly impacting a patient's quality of life. Resveratrol (RES), recognized for its potent antioxidant and anti-inflammatory properties, faces challenges regarding its permeability. This study aimed to develop Resveratrol glycerosomal nanovesicles (RES-GLY-NVs) for topical application to enhance skin permeation. The optimized formulation was integrated into a 2 % HPMC gel and subjected to comprehensive physicochemical characterization, skin deposition, in vitro release, microbiological, antioxidant, and in vivo assessments. Results revealed RES-GLY-NVs with particle size ranging from 82.19 ± 6.51 nm to 145.70 ± 1.39 nm with PDI less than 0.5, encapsulation efficacy ranging from 89.14 ± 1.39 % to 96.09 ± 2.13 % and a zeta potential ranging from −27.93 ± 6.47 mV to −49.33 ± 1.89 mV. The release profile of RES was obviously ranging from % 54.40 ± 1.71 to 77.47 ± 0.54 % after 8 h. In vitro cell assessment revealed that RES-GLY-NVs have no cytotoxicity on normal cells. The optimized RES-GLY-NVs-HPMC gel displayed pseudoplastic rheological behavior and significantly enhanced RES flux and permeability through excised rat skin compared to plain gel. The In vivo study and histological evaluation of diabetic rats ensured that RES-GLY-NVs-HPMC gel acts as a more effective healing adjunct compared to free RES and conventional therapy. These findings encourage the utilization of RES-GLY-NVs-HPMC gel as a wound-healing drug delivery system in chronic diabetes-related wounds and ulcers.

Fibroblasts in Diabetic Foot Ulcers.

Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be "passive cells", solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.

A prospective, blinded, randomized controlled clinical trial evaluating the effect of the synthetic electrospun fiber matrix in the treatment of chronic diabetic foot ulcers

The goal of this randomized, controlled, single-blind clinical trial was to compare the efficacy of synthetic electrospun fiber matrix (SEFM) with standard of care (SOC) in the treatment of diabetic foot ulcers (DFUs). Patients with DFUs ≤30 cm2 were randomized to receive either SEFM (RESTRATA®, Acera Surgical, Inc., St. Louis, MO) or SOC weekly for up to 12 weeks. SOC included foam or alginate dressing changes. The primary endpoint measure was the percentage of wounds achieving 100 % re-epithelialization at 12 weeks. Secondary endpoints included decrease in wound area, time to closure, and number of applications. Forty-six subjects were enrolled and randomized into two groups. In the per protocol (PP) population, 14/19 wounds (74 %) in the SEFM Group demonstrated 100 % re-epithelialization, compared with 6/18 wounds (33 %) in the SOC Group. The proportion of wounds closed and the persistence of wound closure in the SEFM Group was statistically superior to the SOC Group (90 % CI: 0.14, 0.62 / 0.12, 0.65) (Farrington-Manning) in the PP population. Time to complete healing in the SEFM Group (6.6 ± 3.0 weeks) was significantly reduced compared to the SOC Group (p = 0.046, 0.026) (Cox regression) in both the ITT and PP populations. This study represents the first randomized controlled trial to evaluate SEFM in the treatment of chronic DFUs and demonstrates superiority to SOC in achieving 100 % re-epithelialization within 12 weeks. Clinical trial registryNCT04918784.

Management of diabetic foot ulcers using topical probiotics in a soybean-based concentrate: a multicentre study

Objective: Diabetic foot ulcer (DFU) is a common complication in people with diabetes. Standard management includes strict glycaemic management, control of the infection, revascularisation, debridement, mechanical offloading and foot care education. This study aimed to evaluate the efficacy of using topical probiotics in a soybean-based concentrate in the management of DFUs Method: A retrospective, multicentre evaluation of patients with diabetes with non-infected DFUs between October 2020 and October 2021, and who were treated with twice daily topical application of probiotics in a soybean-based concentrate as an adjunct to standard wound care. Results: A total of 22 patients were enrolled into this study, including 16 males and six females, with a mean age of 61 years (range: 31–89 years). Defect size ranged from 1–33.5cm2 (mean: 7.2cm2). The mean number of days until complete healing was 51 (range: 21–112 days). Of the patients, 83% showed complete healing at the end of 16 weeks, 72% showed complete healing at 12 weeks, 56% at eight weeks, and 22% at four weeks. The wounds showed an average decrease in size of 0.59cm2 (9%) per week, calculated using generalised estimating equation. Conclusion: This findings of this study provide a new perspective on the therapeutic potential of probiotics as an effective form of management in patients with small, hard-to-heal (chronic) DFUs.

Healing profiles in patients with a chronic diabetic foot ulcer: An exploratory study with machine learning.

Diabetic foot ulcers (DFU) are one of the most frequent and debilitating complications of diabetes. DFU wound healing is a highly complex process, resulting in significant medical, economicand social challenges. Therefore, early identification of patients with a high-risk profile would be important to adequate treatment and more successful health outcomes. This study explores risk assessment profiles for DFU healing and healing prognosis, using machine learning predictive approaches and decision tree algorithms. Patients were evaluated at baseline (T0; N = 158) and 2 months later (T1; N = 108) on sociodemographic, clinical, biochemical and psychological variables. The performance evaluation of the models comprised F1-score, accuracy, precision and recall. Only profiles with F1-score >0.7 were selected for analysis. According to the two profiles generated for DFU healing, the most important predictive factors were illness representations on T1 IPQ-B (IPQ-B ≤ 9.5 and < 10.5) and the DFU duration (≤ 13 weeks). The two predictive models for DFU healing prognosis suggest that biochemical factors are the best predictors of a favorable healing prognosis, namely IL-6, microRNA-146a-5p and PECAM-1 at T0 and angiopoietin-2 at T1. Illness perception at T0 (IPQ-B ≤ 39.5) also emerged as a relevant predictor for healing prognosis. The results emphasize the importance of DFU duration, illness perception and biochemical markers aspredictorsof healing in chronic DFUs. Future research is needed to confirm and test the obtained predictive models.

The Therapeutic Efficacy of Freeze-Dried Human Amniotic Membrane Allograft Gel for Diabetic Foot Ulcers: A Phase-1 Clinical Trial.

Diabetic foot ulcers (DFUs) are classified as hard-to-heal wounds, which occur in approximately 15% of diabetic patients. Several interventions have shown efficacy in reducing the risk of amputation among patients with DFU, including timely diagnosis and management of infection and ischemia, debridement of necrotic tissues, reducing mechanical pressure on ulcers, and patient education. One major challenge in the management of DFUs is optimizing wound care to improve healing outcomes. Recently, interdisciplinary approaches proposed a new generation of wound dressing which increased efficacy and significantly decreased the healing time. The current study assessed the healing characteristics of chronic DFUs treated with lyophilized amniotic membrane gel (LAMG) in combination with standard care, versus a placebo hydrogel with standard care. In total, 18 patients (8 male, 10 female) were randomly assigned to the control group, which received standard care and a gelatin scaffold (placebo), or the intervention group, which received standard care along with LAMG. We evaluated the reduction in wound size and assessed the patient's health-related quality of life over 9 weeks. In the LAMG group (n = 9) and the Placebo group (n = 9), the wounds were reduced in size by a mean of 73.4% ± 15.3% and 13.1% ± 10.1%, respectively (P = .008). Patients treated with LAMG demonstrated significant improvements in the scores related to physical function, physical limitation, physical pain, general health, social function, emotional problems, and energy levels compared to the control group. The findings of this study indicate that using the LAMG with standard care significantly enhances wound healing.

A Prospective Multicenter Study of a Weekly Application Regimen of Viable Human Amnion Membrane Allograft in the Management of Nonhealing Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) pose a significant clinical challenge for providers and patients, and often precede devastating complications such as infection, hospitalization, and amputation. Therefore, advanced treatment options are needed to facilitate the healing of chronic DFUs and improve outcomes in this high-risk population. Cryopreserved viable human amnion membrane allograft (vHAMA) has shown great promise in the treatment of recalcitrant DFUs as a supplement to standard of care (SOC). Placental grafts are rich in extracellular matrix proteins, growth factors, and cytokines, which can induce angiogenesis and dermal fibroblast proliferation, resulting in accelerated healing. In this prospective, multicenter single arm trial, 20 patients with nonhealing DFUs received weekly application of vHAMA, in addition to SOC, for up to 12 weeks. The primary study endpoint was proportion of healed wounds at 12 weeks. Secondary endpoints included proportion of wounds healed at 6 weeks, time to heal, and percentage area wound reduction. Subjects were evaluated for ulcer healing and assessed for adverse events at every treatment visit. At study conclusion, 85% of patients receiving vHAMA healed. Ten wounds healed (50%) by 6 weeks, and 17 wounds (85%) healed by 12 weeks. The mean time to heal was 46.6 days (95% CI: 35.1-58.0), and the average number of vHAMAs used was 5.4 (SD: 3.25). The mean PAR was 86.3% (SD: 40.51). Aseptically processed, cryopreserved vHAMA should be considered as a safe and effective option for DFUs refractory to SOC therapy.

MicroRNA-27b Impairs Nrf2-Mediated Angiogenesis in the Progression of Diabetic Foot Ulcer.

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a stress-activated transcription factor regulating antioxidant genes, and a deficiency thereof, slowing lymphangiogenesis, has been reported in diabetic foot ulcer (DFU). The mode of Nrf2 regulation in DFU has been less explored. Emerging studies on miRNA-mediated target regulation show miRNA to be the leading player in the pathogenesis of the disease. In the present study, we demonstrated the role of miR-27b in regulating Nrf2-mediated angiogenesis in DFU. A lower expression of mRNA targets, such as Nrf2, HO-1, SDF-1α, and VEGF, was observed in tissue biopsied from chronic DFU subjects, which was in line with miR-27b, signifying a positive correlation with Nrf2. Similarly, we found significantly reduced expression of miR-27b and target mRNAs Nrf2, HO-1, SDF-1α, and VEGF in endothelial cells under a hyperglycemic microenvironment (HGM). To confirm the association of miR-27b on regulating Nrf2-mediated angiogenesis, we inhibited its expression through RNA interference-mediated knockdown and observed disturbances in angiogenic signaling with reduced endothelial cell migration. In addition, to explore the role of miR-27b and angiogenesis in the activation of Nrf2, we pretreated the endothelial cells with two well-known pharmacological compounds-pterostilbene and resveratrol. We observed that activation of Nrf2 through these compounds ameliorates impaired angiogenesis on HGM-induced endothelial cells. This study suggests a positive role of miR-27b in regulating Nrf2, which seems to be decreased in DFU and improves on treatment with pterostilbene and resveratrol.

Perilesional injections of human platelet lysate versus platelet poor plasma for the treatment of diabetic foot ulcers: A double-blinded prospective clinical trial.

Diabetic foot ulcer (DFU) is a major cause of morbidity, non-traumatic lower limb amputation in diabetic patients and a high-cost burden on the healthcare system. New therapeutic products are increasingly tested. Platelet-rich plasma (PRP) and human platelet lysate (hPL) are reported to be useful. This trial was conducted to test whether the healing effect of hPL in chronic DFU was due to plasma or platelet lysates in a prospective double-blind design. Autologous PRP was obtained from citrated blood, lysed, and used as drug 1 (active product). The platelet-poor plasma (PPP) was used as a drug 2 (placebo). Ten patients were enrolled in arm 1 and 9 in arm 2. The drugs were injected perilesionally every 2 weeks for a total of sixinjections. Adverse events were recorded until Week 14. The DFUs were scored per the Texas and Wegner systems. No patient showed any major adverse events. Some reported local pain post-injection. Wound healing was achieved in the hPL group in 9/10 of patients at a mean of 35.1 days. In the PPP group, no patient had healed by Day 84. The difference was statistically significant at P < 0.00001. We conclude that autologous hPL is safe and highly effective in healing chronic DFU and is superior to autologous PPP.

Relax to Heal? Perspectives of Patients with Diabetic Foot Ulcers and Health Professionals on Relaxation Sessions for Wound Healing.

To explore patients' and healthcare professionals' (HPs') perspectives on the suitability/acceptability of a relaxation intervention, its effects on patients' well-being and diabetic foot ulcer (DFU) healing, and its incorporation into the multidisciplinary management of patients with diabetic foot. This qualitative study was nested within a three-arm pilot randomized controlled trial. Patients with a chronic DFU received four relaxation sessions. Investigators then interviewed patients, physicians, and nurses involved with diabetic foot consultations. Interviews were audio-recorded, transcribed, and analyzed using thematic content analysis. Five themes emerged from patient's interviews about the suitability/acceptability of the relaxation intervention: perceptions regarding the psychological intervention, distress, the relaxation technique, changes in the patient's life, and changes in DFU/contribution to healing. Three themes emerged from interviews with HPs: perceptions regarding relaxation, changes in the patient, and changes in DFU/healing. Regarding the feasibility of the relaxation intervention, three themes emerged for both patients and HPs: suggested modifications, stressors/difficulties, and impact of COVID-19 pandemic. The utility theme emerged only in HP interviews, with subthemes of patients' distress, psychological interventions, relaxation intervention, and integration of the psychologist in the team. These findings provide evidence for the suitability/acceptability, feasibility, and utility of a relaxation intervention in diabetic foot consultations.