Ulcer Healing Research Articles

Definitive single-stage surgery for treating diabetic foot osteomyelitis: a protocolized pathway including antibiotic bone graft substitute use.

Diabetic foot ulcers (DFUs) are a challenging complication of diabetes mellitus, often leading to poor clinical outcomes and significant socioeconomic burdens. We evaluated the effectiveness of a definitive single-stage protocolized surgical management pathway, including the use of local antibiotic bone graft substitute, for the treatment of infected DFUs with associated osteomyelitis. A retrospective cohort study was conducted. Medical records were extracted (from January 2017 to December 2020) to establish a database consisting of patients who underwent surgical intervention for the treatment of an infected DFU with osteomyelitis. Patients were divided into conventional (control) and protocolized (intervention) surgical groups depending on the treatment received. Clinical outcomes were assessed over a 12-month follow-up period. A total of 136 consecutive patients were included (conventional = 33, protocolized = 103). The protocolized group demonstrated a statistically significant reduction in the mean number of operations performed per patient (1.2 vs. 3.5) (P < 0.001) and a shorter accumulative hospital length of stay (12.6 vs. 25.1 days) (P < 0.001) compared to the conventional group. Major amputation rates were significantly lower in the protocolized group (2% vs. 18%) (P < 0.001). Within 12 months of surgical intervention, the protocolized group exhibited an ulcer healing rate of 89%, with a low rate of recurrence (3%). The protocolized surgical pathway, including local antibiotic bone graft substitute use, demonstrated superior outcomes compared to conventional management for the treatment of infected DFUs with osteomyelitis. Further research is needed to evaluate the cost-effectiveness and generalizability of this approach.

Letter to the editor "Early identification of delayed wound healing in complex diabetic foot ulcers treated with a dermal regeneration template: a novel clinical target and its risk factors".

Letter to the editor "Early identification of delayed wound healing in complex diabetic foot ulcers treated with a dermal regeneration template: a novel clinical target and its risk factors".

Rifampicin in the Treatment of Refractory Diabetic Foot Ulcer and Diabetic Foot Osteomyelitis-an Observational Study.

Refractory diabetic foot ulcer (rDFU) and osteomyelitis (diabetic foot osteomyelitis [DFO]) are a major problem in people with diabetes. Often resulting from multidrug-resistant polymicrobial infection, these may result in amputation or nonhealing ulcers. In this nonrandomized open-label study, we looked at the outcome of treatment with rifampicin in patients with nonhealing diabetic foot ulcers. Patients with DFUs (n = 67, n = 55 with DFO) unresponsive to conventional antimicrobial therapy for >3 months (rDFU) were taken as the study group. All patients received rifampicin for a minimum of 3 months (maximum 6 months if DUFs did not heal after 3 months) in addition to standard antibiotics and compared with similar kind of DFUs (n = 68, n = 55 DFO) who formed the control group, treated with conventional antimicrobial therapy. Patients were followed up for 12 months. Healing of DFU at 6 months and amputation were primary endpoints of the study. In total, 43 patients (64.2%) in the rifampicin group healed at 3 months and another 4 patients healed when rifampicin was continued for 6 months (n = 47, 70.1%). In the control group, 11 patients healed at 3 months (16.2%) and 25 patients healed at 6 months (36.8%). In total, 14 patients (20.9%) in the study group and 29 patients (42.6%) in the control group had to undergo minor amputation. Comparison between the rate of healing at 3 and 6 months and minor amputation between the study group and control group showed statistically significant results (P ≤ .00001, <.00001, and .008, respectively). In total, 6 and 8 patients despite healing of the primary ulcer had a subsequent recurrence of ulcer in the rifampicin and control group, respectively. Rifampicin used in conjunction with other standard poly-microbial therapy in refractory complex diabetic foot ulcer unresponsive to standard antimicrobial therapy, can significantly improve wound healing as well as decrease the need for amputation in addition to standard of care.

Improving the effect of Topical and Systemic administration of Probiotic Lactobacillus casei Shirota on Interleukin-10 Expression in Traumatic Ulcer Healing in Wistar Rats (Rattus norvegicus)

Improving the effect of Topical and Systemic administration of Probiotic Lactobacillus casei Shirota on Interleukin-10 Expression in Traumatic Ulcer Healing in Wistar Rats (Rattus norvegicus)

Cerium‐based metal–organic frameworks (MOFs) as a sustainable approach to mitigating environmental stress‐induced intestinal ulcers in earthworms

Exposure to environmental stresses such as heavy metal pollution, herbicides, and climate change may cause adverse effects on biological animals such as earthworms, leading to conditions including intestinal ulcers. This study outlines the potential of a cerium‐based metal–organic framework (Ce‐MOF) in healing alcohol‐induced ulcers in earthworms. The Ce‐MOF was synthesized via a solvothermal technique and analyzed using X‐ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. Ce‐MOF exhibited a one‐dimensional channel and demonstrated multi‐enzyme‐like activity. It was examined on earthworms suffering from ulcers caused by alcohol use. Examinations at a macroscopic level, histological analysis, and transmission electron microscopy images showed significant harm to the intestinal lining in ulcerated worms. The ulcer treatment with Ce‐MOF substantially enhanced intestinal morphology, repaired the epithelial lining, and facilitated ulcer healing. Furthermore, Ce‐MOF decreased the death rate and enhanced the weight of earthworms in comparison to untreated groups. This study emphasizes the potential of Ce‐MOF as an innovative therapeutic agent for alcohol‐induced ulcers, emphasizing its prospective uses in regenerative medicine and tissue regeneration.

Healing activity of a muco-adhesive formula of Teucrium polium against acetic acid-induced oral ulcer in rats

Oral ulcers are highly common painful conditions that harmfully affect the quality of life and require long-term therapy. Muco-adhesive preparations provide efficient and convenient delivery systems that prolong the drug retention time necessary for the different stages of ulcer healing. Therefore, the study aimed to evaluate the healing activity of Teucrium polium in a muco-adhesive formula against acetic acid-induced oral ulcers in rats. Acetic acid was applied to the inner cheeks of the rats and the muco-adhesive formula was applied once daily for 14 days. Acetic acid was found to disrupt the oral tissue histological features, increase collagen deposition, induce oxidative stress through increasing malondialdehyde (MDA) levels and decreasing superoxide dismutase and catalase activities, increase the expression of the inflammatory biomarkers, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and decreased hydroxyproline content and the expression of the factors that contribute in wound healing including transforming growth factor-beta1 (TGF-β1), vascular endothelial growth factor receptor 1 (VEGFR1), and platelet-derived growth factor receptor beta (PDGFRβ). However, the daily application of a mucoadhesive formula impregnated with T. polium, significantly restored the regular histological features of the oral tissue, decreased the concentration of MDA, TNF-α, IL-6, and COX-2, increased superoxide dismutase and catalase activities, and restored the expression of TGF-β1, VEGFR1, and PDGFRβ. Therefore, T. polium extract muco-adhesive formula can be considered a potential therapy for chronic oral ulcers.

The use of medical thermal imaging in assessing the dynamics of healing of pressure ulcers in patients with severe brain damage

Patients with severe brain damage often develop pressure ulcers (PU). The phases of the wound process significantly extend in time due to the underlying disease, severity of the condition and metabolic changes. Medical thermal imaging can be used to assess the level of PU microcirculation.Aims: to study the possibility of using medical thermal imaging to predict the course of PU in patients after severe brain damage.Methods: 38 ICU patients after brain injury and stage III–IV PU (25 men, 13 women, mean age 59±17 years). The series of thermograms (native image, after the “cold test” and 3 minutes after) were recorded before treatment and after 21 days. We used an NEC ThermoTracer TH 9100 thermal imager.Results. We assessed the minimum/maximum overall temperatures and in the 1st–4th quartiles. With a positive outcome, the temperatures Q3-Q4 were higher (35.1 C–37.6 C versus 34.8 C–36.7 C for a negative outcome) and the lower thresholds of all quartiles. We hypothesized that a sign of PU healing is a narrowing of the range of temperature points on the surface of the wound. We used a point system for assessing the dynamics of temperature parameters, then checked the model using ROC analysis: the AUC was 0.932 (0.81–1.0), which indicates the high quality. The best ratio of sensitivity and specificity (0.81; 0.83) corresponds to a cut-off point of 9.5.Conclusion. The use of medical thermal imaging makes it possible to objectively assess the level of blood supply to the PU in patients after severe brain damage, as well as the prognosis of further wound healing.

Label-free detection of prostaglandin transporter (SLCO2A1) function and inhibition: insights by wound healing and TRACT assays.

The prostaglandin transporter (PGT, SLCO2A1) mediates transport of prostanoids (a.o. prostaglandin E2 (PGE2)) into cells and thereby promotes their degradation. Overexpression of PGT leads to low extracellular PGE2 levels and has been linked to impaired wound healing of diabetic foot ulcers. Inhibition of PGT could thus be beneficial, however, no PGT inhibitors are currently on the market and drug discovery efforts are hampered by lack of high-through screening assays for this transporter. Here we report on a label-free impedance-based assay for PGT that measures transport activity through receptor activation (TRACT) utilizing prostaglandin E2 receptor subtype EP3 and EP4 that are activated by PGE2. We found that induction of PGT expression on HEK293-JumpIn-SLCO2A1 cells that also express EP3 and EP4 leads to an over 10-fold reduction in agonistic potency of PGE2. PGE2 potency could be recovered upon inhibition of PGT-mediated PGE2 uptake with PGT inhibitors olmesartan and T26A, the potency of which could be established as well. Moreover, the TRACT assay enabled the assessment of transport function of PGT natural variants. Lastly, HUVEC cells endogenously expressing prostanoid receptors and PGT were exploited to study wound healing properties of PGE2 and T26A in real-time using a novel impedance-based scratch-induced wound healing assay. These novel impedance-based assays will advance PGT drug discovery efforts and pave the way for the development of PGT-based therapies.

Human Adipose-Derived Mesenchymal Stem Cells Colonize and Promote Healing of Leprosy Ulcer by Inducing Neuro-Vascularization.

Leprosy ulcer is a chronic and recurrent disease resulting from nerve injury. While existing treatments partially facilitate ulcer healing, they exhibit limited ability to address localized nerve repair, leading to a risk of recurrence. Moreover, there is a dearth of animal models to evaluate the preclinical efficacy and safety of novel therapeutic approaches. Over the years, adipose-derived mesenchymal stem cells have been extensively employed in regenerative medicine as an optimal cell therapy source for fostering skin ulcer healing. They have also demonstrated the capacity to enhance nerve regeneration in in vitro experiments and clinical trials. In this study, we established a NU/NU mouse foot pad leprosy ulcer model, transplanted human adipose-derived stem cells (hADSCs) into leprosy ulcers via local injection, and conducted subsequent follow-up. Our findings revealed that hADSCs persisted in the leprosy ulcer and facilitated the healing process. In this respect, gross observation and histological analysis revealed increased granular formation, collagen synthesis, and re-epithelialization in the local ulcer area. RNA-Seq data revealed that the upregulated differential genes resulting from the transplantation intervention were not only enriched in pathways related to re-epithelialization and collagen synthesis but also contributed to local nerve regeneration. Furthermore, immunofluorescence assays revealed the increased expression of angiogenesis markers-CD31 and VEGFa, cell proliferation markers-Ki67 and TGF-β, and nerve regeneration markers-β3-tubulin, SOX10, NGF, and NT-3. These results underscore the potential of hADSCs in promoting the healing of leprosy ulcers and offer valuable preclinical data for their prospective clinical application.

Management of Dushtavrana (Non-Healing Ulcer) through Ayurveda - A Case Report

Shalyatantra is one among the Astang Ayurveda, the branch of Shalyatantra refers to surgical and parasurgical procedures in Ayurveda. Dusthavrana (non healing ulcer) are a frequently encountered problem in present era produced commonly as a complication of trauma or pathologic insult and it causes long term agony to the patient. The issue of non-healing ulcers management with Ayurvedic remedy is one of the major areas of the research and has come under increased study. This is a case report of 40-year-old female, who had an episode of Dushtavrana (non healing ulcer) and presented to the outpatient department with complaints of severe pain, itching and ulcer over right ankle region. The first line of management for Dushtavrana is Shodhana. Kalka is the specific treatment for Dusthavrana which is mentioned under Shodhana and Ropana Kriya of Saptopakrama. Yavadi Kalka is one of the formulations mentioned in Dwivraniya Chikitsa Adhyaya. Yavadi Kalka is simple, very cost-effective procedure. In the present case, Yavadi Kalka after Jaloukavacharana has shown assuring results in the management of Dushtavrana.

Management of Chronic Persisting Varicose Ulcer Through Modest Ayurvedic Intervention

Varicose ulcer is one of the most common venous disorders which occur as a complication of varicose vein. Venous insufficiency, venous reflux and venous hypertension not only result in dilation and tortuosity of the veins but are also responsible for both dermatological and vascular complication, resulting in the manifestation of varicose ulcer. It is a slow healing chronic recurrent ulcer accounting for almost 80% ulceration of lower extremities. A 50 years old man visited the OPD with complains of pain, swelling, discolouration and wound over the anterior aspect of the left leg above the ankle joint for 6 months. He had a history of varicose vein since 10 years. Six setting of Jalaukavacharan (leech therapy) along with internal administration of Shamana Aushadhi and external cleansing and dressing of ulcer have been done for a period of 1 and a half month. Gradual improvements of symptoms have been observed. The complete ulcer healing evidence has provided an interesting and encouraging result to the scholar and practitioner of this field. The Shamana Aushadhi like Mahamanjisthadi kwath, Kaishor Guggulu, Yastimadhu, Guduchi Sattva and Jalaukavacharan as Sastra karma have showed excellent Vrana Ropaka or ulcer healing effect in a long standing critical venous ulcer.

A conceptual study on clinical application of Pratisaraniya Kshara Karma

Ayurveda indeed delves deep into various therapeutic procedures, including Shastrakarma and Anushstra Karma. Kshara, considered one of the prime therapies, is classified into Paneeya and Pratisarneeya, with the latter further divided into Mridu, Madhyama and Teekshana.[1] Pratisaraniya Kshara involves diverse applications like Kshara application, Kshara Sutra, Kshara Varti, Kshara Plota, Kshara Taila infiltration and intralesional injection of Ksharodaka. Its primary applications encompass treating conditions such as Arsha (hemorrhoids), Bhagandara (fistula-in-ano), Nadivrana (sinus), Vidradhi (abscess), Dustavrana (non healing ulcer) and Charmakeela (warts). In the Sushruta Samhita, Acharya Sushruta elaborates on Kshara's multifaceted actions, attributing qualities like Chedana (cutting), Bhedana (penetrating), Lekhana (scraping), Dahana (caustic action), Pachana (digestive), Darana (breaking down), Vilayana (dissolving), Sodhana (purifying), Ropana (healing) and Stambhana (arresting).[2] Kshara's caustic nature plays a pivotal role in eliminating necrosed and infected tissues by inducing controlled tissue destruction.

Activated carbon cloth versus silver-based dressings in a population with diabetic foot ulcer: a randomised controlled trial.

Activated carbon cloth (ACC), known as Zorflex dressing, has emerged as an innovative approach in managing bacterial infection in diabetic foot ulcer (DFU) treatment. This pilot study was undertaken to determine the efficacy of Zorflex ACC dressing (Chemviron Carbon Cloth Division, UK) compared to standard silver-based dressing on DFUs. An open label, comparative, randomised controlled trial enrolling patients who attended the diabetic foot clinic was conducted between August 2022 and August 2023. The primary endpoint was a difference of 20% in wound area reduction with the ACC dressing compared to silver-based dressing within eight weeks. The secondary endpoints were proportion of complete healing, time to healing and adverse events. The cohort comprised 40 patients. The mean wound reduction percentage at 8 weeks for patients in the ACC arm was 85.40±16.00% compared with 65.08±16.36% in the silver-based dressing arm. Complete healing was observed in six of 20 patients in the ACC arm compared to two of 20 in the silver-based dressing arm. These data suggest that the ACC dressing promotes better ulcer healing in DFU patients than the silver-based dressing.

A randomised Trial of Autologous Blood products, leukocyte and platelet-rich fibrin (L-PRF), to promote ulcer healing in LEprosy: The TABLE trial.

Autologous blood products like Platelet Rich Plasma (PRP) and Leukocyte and Platelets Rich Fibrin (L-PRF) have been used for many years across many types of skin ulcers. However, the effectiveness of autologous blood products on wound healing is not well established. We evaluated the 'second generation' autologous product- Leukocyte and Platelet- Rich Fibrin (L-PRF). Our trial was undertaken on patients suffering from neuropathic leprosy ulcers at the Anandaban hospital which serves the entire country of Nepal. We conducted a 1:1 (n = 130) individually randomised trial of L-PRF (intervention) vs. normal saline dressing (control) to compare rate of healing and time to complete healing. Rate of healing was estimated using blind assessments of ulcer areas based on three different measurement methods. Time to complete healing was measured by the local unblinded clinicians and by blind assessment of ulcer images. The point estimates for both outcomes were favourable to L-PRF but the effect sizes were small. Unadjusted mean differences (intervention vs control) in mean daily healing rates (cm2) were respectively 0.012 (95% confidence interval 0.001 to 0.023, p = 0.027); 0.016 (0.004 to 0.027, p = 0.008) and 0.005 (-0.005 to 0.016, p = 0.313) across the three measurement methods. Time to complete healing at 42 days yielded Hazard Ratios (unadjusted) of 1.3 (0.8 to 2.1, p = 0.300) assessed by unblinded local clinicians and 1.2 (0.7 to 2.0, p = 0.462) on blind assessment. Any benefit from L-PRF appears insufficient to justify routine use in care of neuropathic ulcers in leprosy. ISRCTN14933421. Date of trial registration: 16 June 2020.

Tibial Cortex Transverse Transport Facilitates Severe Diabetic Foot Wound Healing via HIF-1α-Induced Angiogenesis.

Management of severe diabetic foot ulcers (DFUs) remains challenging. Tibial cortex transverse transport (TTT) facilitates healing and limb salvage in patients with recalcitrant DFUs. However, the underlying mechanism is largely unknown, necessitating the establishment of an animal model and mechanism exploration. Severe DFUs were induced in rats, then assigned to TTT, sham, or control groups (n=16/group). The TTT group underwent a tibial corticotomy, with 6 days each of medial and lateral transport; the sham group had a corticotomy without transport. Ulcer healing was assessed through Laser Doppler, CT angiography, histology, and immunohistochemistry. Serum HIF-1α, PDGF-BB, SDF-1, and VEGF levels were measured by ELISA. The TTT group showed lower percentages of wound area, higher dermis thickness (all p < 0.001 expect for p = 0.001 for TTT vs Sham at day 6) and percentage of collagen content (all p < 0.001) than the other two groups. The TTT group had higher perfusion and vessel volume in the hindlimb (all p < 0.001). The number of CD31+ cells (all p < 0.001) and VEGFR2+ cells (at day 6, TTT vs Control, p = 0.001, TTT vs Sham, p = 0.006; at day 12, TTT vs Control, p = 0.003, TTT vs Sham, p = 0.01) were higher in the TTT group. The activity of HIF-1α, PDGF-BB, and SDF-1 was increased in the TTT group (all p < 0.001 except for SDF-1 at day 12, TTT vs Sham, p = 0.005). The TTT group had higher levels of HIF-1α, PDGF-BB, SDF-1, and VEGF in serum than the other groups (all p < 0.001). TTT enhanced neovascularization and perfusion at the hindlimb and accelerated healing of the severe DFUs. The underlying mechanism is related to HIF-1α-induced angiogenesis.

An ex-vivo study to investigate the potential of S. epidermidis lysate to improve wound healing in diabetic foot ulcers

An ex-vivo study to investigate the potential of S. epidermidis lysate to improve wound healing in diabetic foot ulcers

Impact of Great Saphenous Vein Ablation on Healing and Recurrence of Venous Leg Ulcers in Patients with Post-thrombotic Syndrome: A Retrospective Comparative Study

Impact of Great Saphenous Vein Ablation on Healing and Recurrence of Venous Leg Ulcers in Patients with Post-thrombotic Syndrome: A Retrospective Comparative Study

The Effect of Aloe vera on the Healing of Diabetic Foot Ulcer: A Randomized, Double-blind Clinical Trial.

Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that can result in severe consequences. The cost of treating DFUs is high, and there is a lack of new therapies available in developing countries. This has created a demand for complementary and alternative treatments. The objective of this study was to assess the impact of aloe vera gel on the healing process of diabetic foot ulcers. The study was a double-blind, randomized, controlled clinical trial. The study samples were 66 patients with diabetic foot ulcers who were randomly assigned to two groups (intervention and control). All ulcers in both groups were washed with normal saline and dressed in sterile gauze. The ulcers in the intervention group were covered with a thin layer of Aloe Vera gel before the dressing. The Bates-Jensen Wound Assessment Tool (BWAT) was used on three occasions, including before the intervention period and at the end of each week. Data were analyzed using SPSS 16. After three weeks, there was a notable contrast in the recovery pattern of the two groups. The patients who had aloe vera gel added to their dressing showed a more substantial decrease in the mean scores of their BWAT. These findings are promising and suggest that Aloe vera may be a safe and effective adjunctive treatment for diabetic foot ulcers. However, further research is needed to confirm these results and to investigate the underlying mechanisms of aloe vera's therapeutic effect on diabetic foot ulcers.

Effect of Tamarindus indica L. fruit pulp and seed extracts on experimental ulcerative colitis in rats.

Tamarindus indica L. which has anti-inflammatory, radical scavenging, and ulcer healing effects can be useful for the alleviation of inflammatory bowel disease (IBD). Therefore, the effects of T. indica fruit pulp (TIPE) and seed extracts (TISE) were investigated on experimental colitis. TIPE and TISE (125, 250, and 500 mg/kg) were made by maceration (ethanol/water: 80/30) and administered to male Wistar rats with acetic acid-induced colitis. Prednisolone (4 mg/kg) and mesalazine (100 mg/kg) were used as reference drugs. The colon tissues were examined for macroscopic and pathologic parameters and myeloperoxidase (MPO) and malondialdehyde (MDA) values. The total phenols were 45.7 ± 1.1 and 453.0 ± 3.3 mg/g in terms of gallic acid for TIPE and TISE, respectively. Both of the extracts significantly improved most of the investigated parameters including body weight loss, the weight of colons, indices of ulcers, and total colitis. MPO activity and MDA in the treatment groups (except for TIPE at 125 mg/Kg) significantly decreased compared to the control. Both TIPE and TISE were effective in the treatment of colitis however it seems that the effective ingredients were more concentrated in seeds rather than pulp extract so the highest dose of seed extract had a competitive effect with reference drugs. More studies are needed to introduce T. indica as a suitable complementary medicine or food for patients with IBD.

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers.

Diabetes impairs wound healing, notably in diabetic foot ulcers (DFU). Stress, marked by the accumulation of lipoylated mitochondrial enzymes and the depletion of Fe-S cluster proteins, triggers cuproptosis-a distinct form of cell death. The involvement of copper in the pathophysiology of DFU has been recognized, and currently, a copper-based therapeutic strategy is emerging as a viable option for enhancing ulcer healing. This study investigates genes linked to copper metabolism in DFU, aiming to uncover potential targets for therapeutic intervention. Two diabetic wound Gene Expression Omnibus (GEO) datasets were analyzed to study immune cell dysregulation in diabetic wounds. Differentially expressed genes related to copper metabolism were identified and analyzed using machine learning methods. Gene ontology, pathway enrichment, and immune infiltration analyses were performed using DFU samples. The expression of identified genes was validated using qRT-PCR and single-cell RNA sequencing. Ten genes associated with copper metabolism were identified. Among these, SLC31A1 and ADNP were found to be significantly differentially expressed in DFU. Notably, SLC31A1 exhibited higher expression in macrophages, whereas ADNP was found to be highly expressed in fibroblasts and chondrocytes. The study indicates a close link between copper metabolism, the infiltration of immune cells, and DFU. It proposes that copper metabolism could influence the progression of DFU through the activation of immune responses. These observations offer fresh perspectives on the underlying mechanisms of DFU and identify potential targets for therapeutic intervention.