Impaired Wound Healing Research Articles

Exploring the Role of Micrornas in Wound Healing

Wound healing is a complex process involving inflammation, cellular proliferation, and matrix remodeling. However, skin's regenerative capacity varies across species, and adult mammals, including humans, have limited ability to fully regenerate tissue. Scar formation is a common outcome of wound healing, impacting quality of life. MicroRNAs (miRNAs) are key regulators in wound healing, influencing inflammation, cell proliferation, angiogenesis, and matrix remodeling. Dysregulated miRNAs can impair wound healing. Additionally, miRNAs play roles in wound healing, autoimmune diseases, and allergies. Understanding miRNA involvement offers insights into mechanisms and potential therapies for managing these conditions.

Angiopoietin-like 4 promotes epidermal stem cell proliferation and migration and contributes to cutaneous wound re-epithelialization.

Proliferation and migration of epidermal stem cells (EpSCs) are essential for epithelialization during skin wound healing. Angiopoietin-like 4 (ANGPTL4) has been reported to play an important role in wound healing, but the mechanisms involved are not fully understood. Here, we investigate the contribution of ANGPTL4 to full-thickness wound re-epithelialization and the underlying mechanisms using Angptl4-knockout mice. Immunohistochemical staining reveals that ANGPTL4 is significantly upregulated in the basal layer cells of the epidermis around the wound during cutaneous wound healing. ANGPTL4 deficiency impairs wound healing. H&E staining shows that ANGPTL4 deficiency significantly reduces the thickness, length and area of the regenerated epidermis postwounding. Immunohistochemical staining for markers of EpSCs (α6 integrin and β1 integrin) and cell proliferation (PCNA) shows that the number and proliferation of EpSCs in the basal layer of the epidermis are reduced in ANGPTL4-deficient mice. In vitro studies show that ANGPTL4 deficiency impedes EpSC proliferation, causes cell cycle arrest at the G1 phase and reduces the expressions of cyclins D1 and A2, which can be reversed by ANGPTL4 overexpression. ANGPTL4 deletion suppresses EpSC migration, which is also rescued by ANGPTL4 overexpression. Overexpression of ANGPTL4 in EpSCs accelerates cell proliferation and migration. Collectively, our results indicate that ANGPTL4 promotes EpSC proliferation by upregulating cyclins D1 and A2 expressions and accelerating the cell cycle transition from G1 to S phase and that ANGPTL4 promotes skin wound re-epithelialization by stimulating EpSC proliferation and migration. Our study reveals a novel mechanism underlying EpSC activation and re-epithelialization during cutaneous wound healing.

Effect of Au@SiO2 core shell nanoparticles on HG-induced oxidative stress triggered apoptosis in keratinocytes

Growing evidences suggest that excess generation of highly reactive free oxygen/nitrogen radicals (ROS/RNS) are largely due to hyperglycemia causes oxidative stress. Further, excess accumulation of ROS/RNS in cellular compartments aggravates the development and progression of diabetes and its associated complications. Impaired wound healing in diabetic condition is a known vital complication all around the world. Thus, an antioxidant agent having the potential for hindering the oxidative/nitrosative stress triggered diabetic skin complication is required. The present investigation was carried out to understand the impact of silica coated gold nanoparticle (Au@SiO2 NPs) on high glucose (HG)-induced keratinocyte complications. We demonstrated that HG environment enhanced the ROS and RNS accumulations and reduced in cellular antioxidant capacities in keratinocte cells, however, Au@SiO2 NPs treatment restored the HG effect. Furthermore, excess production of ROS/RNS was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential (ΔΨm), and increased in mitochondrial mass, which was restored by Au@SiO2 NPs treatment in keratinocyte cells. In addition, HG-induced excess production of ROS/RNA caused an increased in the biomolecules damage including lipid peroxidation (LPO), and protein carbonylation (PC), 8-oxoguanine DNA glycosylase-1 (OGG1) expression and increased 8-hydroxydeoxyguanosine (8-OHdG) accumulations in DNA, leading to activation of ERK1/2MAPK, AKT and tuberin pathway, inflammatory reaction, and finally apoptotic cell death. In conclusion, our findings showed that Au@SiO2 NPs treatment improved the HG-induced keratinocytes injury by suppressing the oxidative/nitrosative stress, elevating the antioxidant defence system, thereby inhibiting the inflammatory mediators and apoptosis, which may be a therapeutic cure for the diabetic keratinocyte problems.

Bi-layered nanofibers loaded with pomegranate flowers extract as a novel wound dressing: Fabrication, characterization, and in vivo healing promotion

Prolonged and impaired wound healing is a serious complication, and there is an emerging demand for strategies to overcome this problem. In this study, we developed electrospun bilayer nanofibers consisting of a chitosan/PVA active layer loaded with pomegranate flower extract (PFE) and a PCL inactive back layer. Structural, morphological, and physicochemical properties of nanofibers were characterized and wound healing effects of PFE-loaded nanofibers were assessed by in vitro and in vivo experiments, including antibacterial tests, wound closure measurements, and histological and immunohistochemical (IHC) analyses. Nanofibers with optimum formulation showed good hydrophilicity, a mean diameter of 404 nm, and an average roughness of 217 nm. TGA and FTIR studies exhibited typical absorption characteristics of PFE, PCL, and PVA and the compatibility of PFE with the components of bilayer nanofibers. The cumulative amount of PFE released from the monolayer and bilayer fibers after 6 h was measured to be 100% and 64%, respectively, indicating the more sustained release of PFE from bilayer scaffolds. Based on mechanical studies, a more ductile behavior was observed for bilayer fibers than monolayer fibers. The antibacterial assay for PFE-loaded nanofibers exhibited an inhibition zone with a diameter of 19.0 ± 0.5 mm and 15.8 ± 0.3 mm for S. aureus and P. aeruginosa, respectively. PFE-loaded nanofiber exposure contributed to faster wound closure (88% in 14 days) and a significant rise in the expression of α-SMA, CD31, collagen I, and vimentin, indicating a higher tissue regeneration rate for PFE-loaded nanofibers over other treatment groups. In conclusion, bilayer nanofibers containing PFE have a promising potential for wound healing acceleration.

BG04 Oleogel-S10 (birch triterpenes) in the treatment of epidermolysis bullosa wounds: 24-month efficacy and safety data from the EASE study

Abstract Epidermolysis bullosa (EB) is a rare debilitating disorder characterized by skin fragility, blister formation and impaired wound healing. The abnormal wound healing seen in EB is a key driver for systemic disease and can lead to serious clinical complications, deformities and symptoms with a devastating impact on quality of life (QoL). The 90-day double-blind phase (DBP) of the phase III EASE study previously demonstrated accelerated wound healing for oleogel-S10 (birch triterpenes) vs. control gel in EB. Here, we report the safety and total wound burden results from the 24-month open-label phase (OLP), in which all patients received treatment with oleogel-S10. EB Disease Activity and Scarring Index (EBDASI) and body surface area percentage (BSAP) data are reported without visit windows to reflect a real-world situation more accurately, particularly considering the COVID-19 pandemic. The patient population was made up of those with dystrophic EB (n = 178; 86.8%) and junctional EB (n = 25; 12.2%). Further baseline characteristics are available in Table 1. In total, 141 patients (68.8%) completed the OLP. The mean (SD) treatment duration for all patients was 584.7 (246.1) days. Adverse events were reported in 77.1% of all patients in the OLP vs. 81.7% of those receiving oleogel-S10 in the DBP. Mean BSAP for patients treated with oleogel-S10 in the DBP reduced from 12.1% at study entry to 6.1% on completion of the EASE study. Similarly, the mean EBDASI skin activity score in the oleogel-S10 group improved from 19.6 to 15.1 at the end of the OLP. In addition, reductions in both BSAP and EBDASI from OLP baseline were observed in patients who transitioned from control gel to oleogel-S10 in the OLP. Oleogel-S10 has a reassuring long-term safety profile. Furthermore, the long-term impact of accelerated wound healing is evident through the sustained reduction in wound burden over time. This is encouraging given the regular reoccurrence of patients’ fragile wounds in the natural course of this chronic disease. Table 1Baseline characteristics

Impact of corticosteroid administration on the response of exposed dental pulp to capping with bioactive cements-experimental study on mongrel dogs

BackgroundCorticosteroids are commonly used as a treatment for a variety of pathological conditions, however, systemic corticosteroid administration has adverse effects including impaired immune response and wound healing. Such complications may affect pulp healing after direct pulp capping. The current study evaluated the influence of corticosteroids on the healing ability of exposed dogs’ dental pulps after direct pulp capping (DPC) with bioactive materials.MethodsTen healthy male dogs were assigned randomly into two groups, 5 dogs each: group I represent the control group which did not receive any medication, and group II was given corticosteroid for 45 days before DPC and till the dogs were euthanized (n = 75 teeth for each group). Following mechanical exposure, the pulps were randomly capped with either Ca(OH)2, MTA, or Biodentine. The pulpal tissues’ reaction to the capping materials was evaluated 65 days postoperatively according to the following parameters: calcific bridge formation, pulpal inflammation, pulp necrosis, and bacterial infiltration.ResultsThe corticosteroid-treated group revealed no significant difference compared to the control group concerning the pulp healing response (P > 0.05). Both Biodentine and MTA-treated specimens revealed significant differences with Ca(OH)2-treated specimens (P < 0.05) which displayed a superior positive effect of both MTA and Biodentine to Ca(OH)2 regarding all the parameters.ConclusionsDirect pulp capping technique whenever indicated in subjects treated with corticosteroid immunosuppressive drugs like prednisone performed well in aseptic conditions especially when capped with bioactive materials.

Panthenol Citrate Biomaterials Accelerate Wound Healing and Restore Tissue Integrity.

Impaired wound healing is a common complication for diabetic patients and effective diabetic wound management remains a clinical challenge. Furthermore, a significant problem that contributes to patient morbidity is the suboptimal quality of healed skin, which often leads to reoccurring chronic skin wounds. Herein, a novel compound and biomaterial building block, panthenol citrate (PC), is developed. It has interesting fluorescence and absorbance properties, and it is shown that PC can be used in soluble form as a wash solution and as a hydrogel dressing to address impaired wound healing in diabetes. PC exhibits antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic properties, and promotes keratinocyte and dermal fibroblast migration and proliferation. When applied in a splinted excisional wound diabetic rodent model, PC improves re-epithelialization, granulation tissue formation, and neovascularization. It also reduces inflammation and oxidative stress in the wound environment. Most importantly, it improves the regenerated tissue quality with enhanced mechanical strength and electrical properties. Therefore, PC could potentially improve wound care management for diabetic patients and play a beneficial role in other tissue regeneration applications.

Therapy of pathological scars.

A scar develops following the appearance of a deep tissue defect as part of the physiological wound healing process. The initial inflammatory response is followed by proliferation of connective tissue cells, which form fibrosis as a final tissue substitute. Disorders can occur at all stages of the process and are most commonly manifested as impaired wound healing or the formation of atrophic and hypertrophic scars or keloids. The focus of this article is on the treatment of pathologic scars, which are an indication for therapy due to functional limitations, complaints, and stigmatization, among other reasons. Conservative medical, physical, surgical and laser therapeutic approaches are pursued. The basis for this is an understanding of the pathophysiological mechanisms and factors influencing the choice of therapy, as well as an interdisciplinary and interprofessional therapeutic approach.

Current data regarding homeostasis of tissues oxygenation in pathophysiological and therapeutic circumstances

Abstract: Oxygen is essential for cellular respiration and energy production. Tissue oxygenation refers to delivering oxygen to cells throughout the body. Microcirculation brings blood through small sanguine vessels to maintain the cells' supply of nutrients and oxygen. Optimal tissue ox-ygenation and microcirculation are essential for maintaining healthy tissue. Conversely, poor oxygenation can cause tissue damage, impair wound healing, and increase infection risk. Several factors can affect tissue oxygenation and microcirculation, including age, lifestyle factors (such as smoking and stress), and underlying medical conditions (such as diabetes and high blood pres-sure). To improve tissue oxygenation and microcirculation, individuals can engage in healthy lifestyle habits such as regular exercise, healthy eating, stress management, and avoiding smoking. Tissue oxygenation can also be looked therapeutic, given that topical and cosmetic treatments such as massage, pelotherapy, hydrotherapy, moisturizers, and certain skin care products can help promote healthy microcirculation at the somatic level. In the scientific literature, the focus is on hypoxia rather than tissue oxygenation. This article proposes a paradigm shift and emphasizes the homeostatic importance of microcirculation and tissue oxygenation in pathophysiological and therapeutic circumstances. The systematic review of the data from the last 2 years (2021-2022) and the meta-analysis performed on tissue oxygenation will contribute to the practical approach to the pathology circumscribed to tissue oxygenation. Keywords: Tissue oxygenation; Hypoxia; Microcirculation; Homeostasis; Microenvironment

Stromal vascular fraction gel promoted wound healing and peripheral nerve repair in diabetic rats via TLRs/MyD88/NF-κB signaling pathway.

Diabetes mellitus (DM) contributes to impaired wound healing. This study was aimed to evaluate the effect of stromal vascular fraction (SVF) gel extracted from rats on diabetic ulcers wound healing and peripheral nerve repair. 60 Sprague Dawley (SD) rats were divided into 6 groups, including control, model, SVF-gel low dose (SVF-gel-L), SVF-gel high dose (SVF-gel-H), ST2825, and SVF-gel-H + CL075 groups. Wound closure rate was recorded. The histopathological changes and deposition change of collagen fibre were identified. The content of TNF-α, IL-1β, VEGF, and bFGF were detected. Immunohistochemical, immunofluorescence and western blot were employed to determine the protein expression. We identified SVF-gel could promoted wound healing, restored normal cutaneous structures of the wound, promoted collagen deposition, while diminished fibrosis and inflammation. In addition, SVF-gel promoted angiogenesis and peripheral nerve recovery, diminished the expression of TLRs/MyD88/NF-κB signaling pathway. However, the protective effect of SVF-gel could be revised by CL075 co-treatment. Furthermore, ST2825 also promoted wound healing, but its effect was lower than that with SVF-gel-H treatment. SVF gel promotes the healing of diabetic skin ulcer tissue and regeneration of damaged peripheral nerve, diminished inflammatory factor infiltration. The mechanism maybe related to suppress the activation of TLRs/MyD88/NF-κB signaling pathway.

29-OR: Diabetic Wound Keratinocytes Induce Macrophage JMJD3–Mediated Nlrp3 Expression

Macrophage (Mφ) plasticity is critical for normal wound repair; however, type 2 diabetic (T2D) wound Mφs display a delayed chronic inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome gene expression and activation in Mφs contributes to impaired wound healing in T2D and is induced by diabetic wound environment factors, yet the molecular mechanisms regulating this are unclear. Our lab has shown that keratinocytes, structural cells in the skin, regulate skin inflammation and Mφ phenotype during wound healing by preferentially producing proinflammatory cytokines. Thus, this project explores the molecular mechanisms by which keratinocytes drive increased Nlrp3 expression in diabetic wound Mφs. Here, we found that Nlrp3 expression is increased in diabetic wound Mφs late post-injury, and this can be induced by stimulation of normal wound Mφs with diabetic wound keratinocyte supernatant. Further, we found that stimulation of Mφs with diabetic wound keratinocyte supernatant resulted in decreased H3K27me3 deposition at the Nlrp3 promoter. Using genetically engineered mice (Jmjd3 fl/fl lyz2cre), we demonstrate that JMJD3, a demethylase specific for H3K27, controls Mφ-mediated Nlrp3 expression and inflammasome activation during wound healing. Importantly, we show that diabetic wound keratinocytes induce Jmjd3 expression in Mφs via IL1 receptor and MyD88 upstream signaling. Interestingly, we found that IL1α is increased in human and murine wound diabetic keratinocytes compared to nondiabetic controls and stimulation of Mφs with IL1α increases Nlrp3 expression via a H3K27me3/JMJD3-mediated mechanism. Thus, our data suggest a role for keratinocyte IL1α in driving increased Nlrp3 expression in chronic diabetic wound Mφs via JMJD3. Continued investigation into the dysregulation of the keratinocyte-Mφ axis in diabetic wounds is key to developing novel treatments for non-healing wounds in T2D patients. Disclosure S. Wolf-Fortune: None. J. Moon: None. A. Joshi: None. P. Mazumder: None. E. Barrett: None. K.D. Mangum: None. K. Gallagher: None. Funding National Institutes of Health (1K99DK133828-01, P30DK089503, R01HL137919, R01DK124290, R01HL15627401, R01DK127531)

A case of nontraumatic simultaneous bilateral Achilles tendon rupture.

Patients with corticosteroid-managed chronic obstructive pulmonary disease (COPD) are at increased risk of Achilles tendon rupture. This risk is further augmented in the setting of an acute COPD exacerbation in which antibiotics may be indicated, namely fluoroquinolones. This case concerns a 76-year-old man who experienced simultaneous nontraumatic bilateral Achilles tendon rupture during an acute COPD exacerbation. Treatment was conservative with analgesics, activity modification, and bilateral controlled ankle movement boots. Surgery was not advised because of his multiple medical comorbidities predisposing him to impaired wound healing and potential amputation. Included is a discussion on the pathophysiology, diagnosis, and treatment of Achilles tendon rupture. There is a need for greater awareness of the risk of Achilles tendon rupture from combined use of corticosteroids and fluoroquinolones. After this report, we hope to raise awareness of this complication and prevent patient suffering.

#5768 ASSOCIATION OF HIGH SERUM PHOSPHORUS WITH INCREASED MORTALITY RISK IN PATIENTS ON PERITONEAL DIALYSIS: RESULTS FROM COLOMBIA

Abstract Background and Aims Elevated levels of serum phosphorus (PO4) in patients with kidney failure are associated with complications such as cardiovascular (CV) disease, bone disease and impaired wound healing, and increased mortality in hemodialysis patients. A recent PDOPPS study (Lopes et al NDT 2023) showed that high PO4 is associated with increased mortality also in patients undergoing peritoneal dialysis (PD). We explored PO4 levels in a large cohort of patients undergoing chronic PD in Colombia to determine the association of PO4 levels with mortality. Method In an observational study of 8113 prevalent PD patients treated with APD (n = 2692) or CAPD (n = 5421), PO4 levels together with demographic and clinical data, including dialysate to plasma ratio of creatinine at 240 min (D/PCr240min at peritoneal equilibration test) and body mass index (BMI), were recorded. During follow-up for a median of 1.99 years, 3169 patients died, and 988 patients underwent kidney transplantation (KT). We divided patients into 5 groups (P1 to P5) according to their baseline PO4 levels (first available measurement) with the following cut-off values for groups: up to 3.5, 4.5, 5.5, 6.5, and over 6.5 mg/dL, respectively. The association of baseline PO4 levels with all-cause and CV mortality risk was analyzed with a competing-risk regression model and KT as a competing risk. Results Characteristics of patients classified into groups P1 (16%), P2 (33%), P3 (27%), P4 (13%), and P5 (9%) are presented in Table. P5-patients were in general younger, more often men, less often diabetic (DM), and had lower hemoglobin (Hb) and serum albumin compared to P1-patients. All-cause mortality risk (after adjusting for age, sex, BMI, albumin, Hb, D/PCr240min, residual renal function, DM, and hypertension) was increased in P4- and P5-patients compared with P2-patients, sub-hazard ratio (sHR) of 1.14 (95% Cl: 1.01-1.27) and sHR of 1.27 (95% Cl: 1.10-1.46), respectively. Higher PO4 levels were not associated with significantly increased CV mortality risk for P4-patients, sHR of 1.10 (95% Cl: 0.93-1.31), or for P5-patients, sHR = 1.14 (95% Cl: 0.93-1.39) compared to P2-patients. Conclusion Among 8113 PD patients in Colombia, 49% had baseline PO4 &amp;gt;4.5 mg/dL and 22% PO4 &amp;gt; 5.5 mg/dL. Baseline PO4 levels &amp;gt; 5.5 mg/dL (P4 and P5 groups) were associated with increased all-cause mortality. These results are in agreement with the results of the PDOPPS study and suggest that effective management of hyperphosphatemia is important to improve clinical outcomes in PD patients.

Topical Dihydroartemisinin Improves Wound Healing in Diabetic Mice.

Impaired skin wound healing is a common complication of diabetes mellitus. Angiogenesis is a critical step in wound healing because it allows oxygen and nutrients to reach the injured area, thereby promoting wound cell proliferation, re-epithelialisation, and collagen regeneration. However, the neovascularisation ability of patients with diabetes often decreases. Therefore, finding ways to improve diabetic angiogenesis is important for treating diabetic wounds that do not heal. To the best of our knowledge, it is unclear whether dihydroartemisinin (DHA) affects diabetic wounds. This study sought to determine how topical DHA affects the healing of diabetic wounds and how it is related to markers of angiogenesis. We topically applied DHA to full-thickness cutaneous lesions in a streptozotocin (STZ)-induced diabetic mouse model. Under a fluorescence microscope, the pathological morphology of the wound skin was observed, together with the positive expression of platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF). Western blotting was used to determine the CD31 and VEGF protein expression levels. The mRNA expression was determined using qualitative real-time polymerase chain reaction (qRT-PCR). We found that DHA can improve the expression of CD31 and VEGF, and accelerate wound healing in diabetic mice. We believe that DHA promotes angiogenesis, which is associated with increased VEGF signalling in vivo. Therefore, DHA can effectively accelerate the process of diabetic wound healing by promoting angiogenesis, implying that DHA may be used as a topical drug for the treatment of diabetic wounds.

MDB-40. TRANSCRIPTOME-BASED DRUG REPURPOSING IN GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is divided into four molecular subgroups (SHH, WNT, Group 3 [G3], and Group 4 [G4]), each defined by unique genetic and molecular features. G3MB is the most aggressive subgroup, with the lowest five-year survival. Features conferring high risk to G3MB include frequent metastases at diagnosis, MYC amplification, and chromosome i17q. Outcomes for G3MB patients remain dismal, partly due to a lack of G3MB-specific therapies, defining an important gap in MB research. To address this gap, we employed a strategy of comparing the G3MB transcriptomic signature against a repository of chemical perturbagens (LINCS) to identify FDA-approved, blood-brain barrier penetrant drugs capable of reverting the disease signature to a more normal cerebellum-like state. Following preliminary in silico and in vitro screening, we identified four drugs - fluoxetine, sertraline, simvastatin, and nortriptyline - that passed screening criteria and demonstrated cytotoxicity against HDMB03 cells at low micromolar doses. Each compound also inhibited clonogenicity, impaired wound healing, and impeded cell migration and invasion. Further, each compound induced apoptosis as evidenced by annexin V and propidium iodide staining. Western blotting confirmed both dose- and time-dependent increases in the expression of key apoptotic markers. Since nortriptyline possessed the best cytotoxicity profile against HDMB03 cells, we interrogated the transcriptome of HDMB03 cells treated with nortriptyline to identify cancer-related pathways inhibited by drug treatment. Our data revealed strong inhibition of E2F transcription factors, which are critical to cancer cell cycle progression and proliferation. Notably, five of the six E2F transcription factors as well as a panel of E2F target genes (HN1, KIF4A, CDCA3, CDCA8, and SSRP1) are all specifically upregulated in G3MB. This study highlights the promise of drug discovery and repurposing using subgroup-specific transcriptomes, which may deliver effective treatments expeditiously to high-risk patients.

E-cadherin and aquaporin-3 are downregulated in wound edges of human chronic wounds.

Chronic wounds are defined as wounds that fail to proceed through the normal phases of wound healing; a complex process involving different dynamic events including migration of keratinocytes in the epidermis. Chronic wounds are estimated to affect 1-2% of the human population worldwide and are a major socioeconomic burden. The prevalence of chronic wounds is expected to increase with the rising number of elderly and patients with diabetes and obesity, who are at high risk of developing chronic wounds. Since E-cadherin and the water channel aquaporin-3 are important for both skin function and cell migration, and aquaporin-3 is furthermore involved in wound healing of the skin demonstrated by impaired wound healing in aquaporin-3-null mice, we hypothesized that E-cadherin and aquaporin-3 expression may be dysregulated in chronic wounds. Therefore, we investigated the expression of E-cadherin and aquaporin-3 in biopsies from the edges of chronic wounds from human patients. This was accomplished by immunohistochemical stainings of E-cadherin and aquaporin-3 on serial sections followed by qualitative evaluation of staining patterns, which revealed low expression of both E-cadherin and aquaporin-3 at the wound edge. Future studies are needed to reveal if this downregulation is associated with the pathophysiology of chronic wounds.

Engineered bacteria to accelerate wound healing: an adaptive, randomised, double-blind, placebo-controlled, first-in-human phase 1 trial.

Impaired wound healing is a growing medical problem and very few approved drugs with documented clinical efficacy are available. CXCL12-expressing lactic acid bacteria, Limosilactobacillus reuteri (ILP100-Topical), has been demonstrated to accelerate wound healing in controlled preclinical models. In this first-in-human study, the primary objective was to determine safety and tolerability of the drug candidate ILP100-Topical, while secondary objectives included assessments of clinical and biologic effects on wound healing by traditionally accepted methods and explorative and traceable assessments. SITU-SAFE is an adaptive, randomised, double-blind, placebo-controlled, first-in-human phase 1 trial (EudraCT 2019-000680-24) consisting of a single (SAD) and a multiple ascending dose (MAD) part of three dose cohorts each. The study was performed at the Phase 1 Unit, Uppsala University Hospital, Uppsala, Sweden. Data in this article were collected between Sep 20th, 2019 and Oct 20th 2021. In total 240 wounds were induced on the upper arms in 36 healthy volunteers. SAD: 12 participants, 4 wounds (2/arm), MAD: 24 participants, 8 wounds (4/arm). Wounds in each participant were randomised to treatment with placebo/saline or ILP100-Topical. In all individuals and doses, ILP100-Topical was safe and well-tolerated with no systemic exposure. A combined cohort analysis showed a significantly larger proportion of healed wounds (p=0.020) on Day 32 by multi-dosing of ILP100-Topical when compared to saline/placebo (76% (73/96) and 59% (57/96) healed wounds, respectively). In addition, time to first registered healing was shortened by 6 days on average, and by 10 days at highest dose. ILP100-Topical increased the density of CXCL12+ cells in the wounds and local wound blood perfusion. The favourable safety profile and observed effects on wound healing support continued clinical development of ILP100-Topical for the treatment of complicated wounds in patients. Ilya Pharma AB (Sponsor), H2020 SME Instrument Phase II (#804438), Knut and Alice Wallenberg foundation.

Immune Fitness, Migraine, and Headache Complaints in Individuals with Self-Reported Impaired Wound Healing.

Having chronic wounds and impaired wound healing are associated with psychological distress. The current study aims to evaluate migraine and headache complaints in young adults with self-reported impaired wound healing. A survey was conducted among N=1935 young adults (83.6% women), 18-30 years old, living in the Netherlands. Wound healing status was verified, immune fitness was assessed using a single-item rating scale, and ID Migraine was completed. In addition, several questions were answered on past year's headache experiences (including frequency, quantity, type, location, and severity). In both the control group (p < 0.001) and the IWH group (p = 0.002) immune fitness was significantly lower among those that reported headaches compared to those that reported no headaches. Individuals with self-reported impaired wound healing (IWH) scored significantly higher on the ID Migraine scale, and individuals of the IWH group scored significantly more often positive for migraine (ie, an ID Migraine score ≥2). They reported a younger age of onset of experiencing headaches, and significantly more often reported having a beating or pounding headache than the control group. Compared to the control group, the IWH group reported being significantly more limited in their daily activities compared to the control group. Headaches and migraines are more frequently reported by individuals with self-reported impaired wound healing, and their reported immune fitness is significantly poorer compared to healthy controls. These headache and migraine complaints significantly limit them in their daily activities.

Management of Radiation-induced Tissue Injuries: A Review of Current Treatment Strategies.

A literature search was performed on PubMed to review the current described management and treatment options for radiation-induced injuries. Patient demographics, medical diagnoses, complications, strategies of management care, and outcomes were reviewed. The most commonly described management options and reconstructive techniques of radiation wounds were analyzed and reported. Consideration of current techniques and outcomes in the management of radiation-induced wounds demonstrates that impaired wound healing remains a major problem. This literature review provides a detailed overview of the most frequently used therapies with recommendations for surgeons.

A topical formulation of Anacardium occidentale L. leaves extract enhances wound healing via mediating TNF-α and TGF- β

Repeated trauma, inadequate perfusion or oxygenation, excessive inflammation, infection, oxidative stress, anddiabetes all contribute to impaired wound healing. In a clinical setting, delay in healing may result in severe complicationssuch as gangrene, leading to extended hospitalization, amputation and even death of the patient. Slow wound healing andlimitations of currently available synthetic medication, urges the need for a safe, affordable, patient-friendly, andmulti-modal herbal wound care agent. Anacardium occidentale L., commonly known as cashew and locally, Kaju, isreported to possess antidiabetic, antibacterial, antioxidant, anti-inflammatory and antiulcerogenic activities. In this study, weevaluated the wound healing activity of gel containing the extract of A. occidentale leaves in rats using incision, excisionand dead space wound models. Increased wound contraction, breaking strength, hydroxyproline and hexosamine content,TGF-β level and decreased level of TNF-α indicated that the developed gel accelerated the wound healing process.Moreover, the docking studies indicated that the aqueous alcoholic extract exerted healing activity by inhibiting GSK3-βthrough β-catenin dependent Wnt signaling pathway. Thus, it can be concluded that the Anacardium occidentale leavesextract can be a potential wound healing agent by acting on various phases of healing process.