Ligustilide covalently binds to Cys703 in the pre-S1 helix of TRPA1, blocking the opening of channel and relieving pain in rats with acute soft tissue injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The natural anodyne Ligustilide (Lig), derived from Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort., has been traditionally employed for its analgesic properties in the treatment of dysmenorrhea and migraine, and rheumatoid arthritis pain. Despite the existing reports on the correlation between TRP channels and the analgesic effects of Lig, a comprehensive understanding of their underlying mechanisms of action remains elusive. AIM OF THE STUDY: The objective of this study is to elucidate the mechanism of action of Lig on the analgesic target TRPA1 channel. METHODS: The therapeutic effect of Lig was evaluated in a rat acute soft tissue injury model. The analgesic target was identified through competitive inhibition of TRP channel agonists at the animal level, followed by Fluo-4/Ca2+ imaging on live cells overexpressing TRP proteins. The potential target was verified through in-gel imaging, colocalization using a Lig-derived molecular probe, and a drug affinity response target stability assay. The binding site of Lig was identified through protein spectrometry and further analyzed using molecular docking, site-specific mutation, and multidisciplinary approaches. RESULTS: The administration of Lig effectively ameliorated pain and attenuated oxidative stress and inflammatory responses in rats with soft tissue injuries. Moreover, the analgesic effects of Lig were specifically attributed to TRPA1. Mechanistic studies have revealed that Lig directly activates TRPA1 by interacting with the linker domain in the pre-S1 region of TRPA1. Through metabolic transformation, 6,7-epoxyligustilide (EM-Lig) forms a covalent bond with Cys703 of TRPA1 at high concentrations and prolonged exposure time. This irreversible binding prevents endogenous electrophilic products from entering the cysteine active center of ligand-binding pocket of TRPA1, thereby inhibiting Ca2+ influx through the channel opening and ultimately relieving pain. CONCLUSIONS: Lig selectively modulates the TRPA1 channel in a bimodal manner via non-electrophilic/electrophilic metabolic conversion. The epoxidized metabolic intermediate EM-Lig exerts analgesic effects by irreversibly inhibiting the activation of TRPA1 on sensory neurons. These findings not only highlight the analgesic mechanism of Lig but also offer a novel nucleophilic attack site for the development of TRPA1 antagonists in the pre-S1 region.

Stem cell­mediated modulation of pyroptosis contributes to tissue repair in noninfective inflammatory­related diseases (Review).

Pyroptosis, a programmed cell death marked by lytic and inflammatory characteristics, plays a crucial role in non­infectious inflammation­related diseases but can lead to detrimental outcomes when dysregulated. Stem cells have emerged as key players in modulating pyroptosis through paracrine signaling, offering a novel avenue for tissue repair and regeneration. The present review delved into previous studies elucidating the intricate interplay between stem cells and pyroptosis, emphasizing the potential of stem cell­based therapies in regulating pyroptotic pathways. The exploration of this dynamic interaction holds promise for developing strategies to harness stem cells for effective tissue repair and regeneration in the context of inflammation­related diseases.

[The secretome of mesenchymal stromal cells as a new hope in the treatment of acute brain tissue injuries]. / Sekretom mezenkhimnykh stromal'nykh kletok kak novaya nadezhda v lechenii ostrykh povrezhdenii golovnogo mozga.

Ischemic and hemorrhagic strokes, traumatic brain injury, bacterial and viral encephalitis, toxic and metabolic encephalopathies are very different pathologies. But, they have much more in common than it might seem at first glance. In this review, the authors propose to consider these brain pathologies from the point of view of the unity of their pathogenetic mechanisms and approaches to therapy. Particular attention is paid to promising therapeutic approaches, such as therapy using cells and their secretion products: an analysis of the accumulated experimental data, the advantages and limitations of these approaches in the treatment of brain damage was carried out. The review may be of interest both to specialists in the field of neurology, neurosurgery and neurorehabilitation, and to readers who want to learn more about the progress of regenerative biomedicine in the treatment of brain pathologies.

Current Insights into Tissue Injury of Giant Cell Arteritis: From Acute Inflammatory Responses towards Inappropriate Tissue Remodeling.

Giant cell arteritis (GCA) is an autoimmune disease affecting large vessels in patients over 50 years old. It is an exemplary model of a classic inflammatory disorder with IL-6 playing the leading role. The main comorbidities that may appear acutely or chronically are vascular occlusion leading to blindness and thoracic aorta aneurysm formation, respectively. The tissue inflammatory bulk is expressed as acute or chronic delayed-type hypersensitivity reactions, the latter being apparent by giant cell formation. The activated monocytes/macrophages are associated with pronounced Th1 and Th17 responses. B-cells and neutrophils also participate in the inflammatory lesion. However, the exact order of appearance and mechanistic interactions between cells are hindered by the lack of cellular and molecular information from early disease stages and accurate experimental models. Recently, senescent cells and neutrophil extracellular traps have been described in tissue lesions. These structures can remain in tissues for a prolonged period, potentially favoring inflammatory responses and tissue remodeling. In this review, current advances in GCA pathogenesis are discussed in different inflammatory phases. Through the description of these-often overlapping-phases, cells, molecules, and small lipid mediators with pathogenetic potential are described.

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study.

BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. METHODS: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). RESULTS: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1ß was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1ß after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1ß and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). CONCLUSIONS: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

Efficacy and safety of Wuhu oral liquid in treating acute soft tissue injuries: a multicenter, randomized, double-blind, double-dummy, parallel-controlled trial.

Background: Wuhu Oral Liquid (WHOL) is a modified preparation derived from the famous Wuhu Powder, which has a long history of use in treating traumatic injuries. This preparation has anti-inflammatory and analgesic properties and accelerates recovery following acute soft tissue injuries. Aims: To evaluate the efficacy and safety of WHOL in treating acute soft tissue injury associated with qi stagnation and blood stasis syndrome and to provide a basis for applying for the protection of varieties of Chinese medicine for WHOL. Methods: This study was a randomized, controlled, double-blind, multicenter clinical trial in which Fufang Shang Tong Capsule (FFSTC) was selected as the control drug. A total of 480 subjects with acute soft tissue injury associated with qi stagnation and blood stasis syndrome were randomly divided into a test and control group in a 3:1 ratio. The duration of drug treatment was 10 days. The primary outcome was Visual Analogue Scale (VAS) score for pain (including pain at rest and pain on activity). Secondary outcomes included the disappearance time of the pain at rest and on activity; the curative effect of TCM syndrome and improvement in the individual symptoms of TCM (swelling, ecchymosis, and dysfunction); and changes in C-reactive protein (CRP) and interleukin-6 (IL-6) levels. Safety was assessed using vital signs, laboratory examinations, electrocardiograms, and physical examinations. Results: Patient compliance was satisfactory in both groups (all between 80% and 120%). After 4 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain at rest (-1.88 ± 1.13 vs. -1.60 ± 0.93, p < 0.05) and on activity (-2.16 ± 1.18 vs. -1.80 ± 1.07, p < 0.05). After 7 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain on activity (-3.87 ± 1.60 vs. -3.35 ± 1.30, p < 0.01) and improving swelling (cure rate: 60.4% vs. 46.2%, p < 0.05; obvious effective rate: 60.7% vs. 47.0%, p < 0.05). After 10 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the levels of CRP (-0.13 ± 2.85 vs. 0.25 ± 2.09, p < 0.05) and improving the TCM syndrome (cure rate: 44.1% vs. 30.8%, p < 0.05) and swelling (cure rate: 75.6% vs. 67.5%, p < 0.01; obvious effective rate: 75.6% vs. 68.4%, p < 0.05; effective rate: 77.0% vs. 71.8%, p < 0.05). The disappearance time of pain at rest was 8 days in both groups and 9 days on activity in both groups. In addition, there was no statistical difference between the incidence of adverse events (4.5% vs. 2.6%, p > 0.05) and adverse reactions (0.3% vs. 0%, p > 0.05) between the WHOL group and the FFSTC group. No serious adverse events occurred in either group, and no subjects were withdrawn because of adverse events. Conclusion: WHOL relieves the symptoms caused by acute soft tissue injury associated with qi stagnation and blood stasis syndrome more rapidly than FFSTC, and it is effective and safe in the treatment of acute soft tissue injury. Future studies still need a larger sample size to verify its efficacy and safety. Clinical Trial Registration: https:// www.chictr.org.cn/showproj.html?proj=149531, Identifier ChiCTR2200056411.

The Medium-Term Outcomes of Patients With Suspected Scaphoid Fractures: A Single-Centre Retrospective Cohort Study.

Background The medium-term outcomes of patients (six to 14 months post-injury) with non-specific wrist injuries managed as suspected scaphoid fractures are not clear from the current literature. These patients' wrists are immobilized in casts or splints, and some receive physiotherapy. They receive serial imaging and follow-up appointments as needed. Aims This study aims to describe the medium-term outcomes of patients with non-specific wrist injuries managed as suspected scaphoid fractures. Methods This is a single-centre retrospective cohort study. Patients with suspected scaphoid fractures were identified from a consecutive database and were included. Patients diagnosed with a definitive scaphoid fracture at any point in time were excluded. Patients with any pre-existing wrist pathology were also excluded. In total 113 patients were posted the Patient-Rated-Wrist-Evaluation (PRWE) questionnaire at six to 14 months post-injury with a self-addressed return envelope. Demographic and PRWE data were collated and described.  Results Twenty-two patients (19% of total patients) returned a completed questionnaire. The median PRWE score was 32 out of 100 indicating mild pain and disability. 45.5% of patients were in this category. A minority of patients (9%) continued to suffer severe or very severe pain and disability. Patients with PRWE scores <40, representing pain and disability that is mild or less, reported very low difficulty completing work and recreational activities. Patients tended not to have pain at rest and experienced the most difficulty lifting heavy objects.  Conclusion Most patients with non-specific wrist injuries managed as suspected scaphoid fractures experience some pain and disability in the medium term. For most this is minimal or mild, however some patients experience significant pain and disability. This study adds to existing evidence that this is the case. The reasons why these patients suffer are unclear. This study highlights the need to refine clinical practice to improve the outcomes of these patients.

Can Shockwave Treatment Elicit a Molecular Response to Enhance Clinical Outcomes in Pressure Ulcers? The SHOck Waves in wouNds Project.

Wound healing requires the coordinated interaction of dermis cells, the proper deposition of extracellular matrix, re-epithelialization, and angiogenesis. Extracorporeal shock wave (ESW) is a promising therapeutic modality for chronic wounds. This study determined the biological mechanisms activated under ESW, facilitating the healing of pressure ulcers (PUs). A group of 10 patients with PUs received two sessions of radial ESW (300 + 100 pulses, 2.5 bars, 0.15 mJ/mm2, 5 Hz). Histomorphological and immunocytochemical assessments were performed on tissue sections obtained from the wound edges before the ESW (M0) and after the first (M1) and second (M2) ESW. The proliferation index of keratinocytes and fibroblasts (Ki-67), the micro-vessels' density (CD31), and the number of myofibroblasts (α-SMA) were evaluated. The involvement of the yes-associated protein (YAP1) in sensing mechanical strain, and whether the nuclear localization of YAP1, was shown. The increased proliferative activity of epidermal cells and skin fibroblasts and the increased number of myofibroblasts, often visible as integrated cell bands, were also demonstrated as an effect of wound exposure to an ESW. The results indicate that the major skin cells, keratinocytes, and fibroblasts are mechanosensitive. They intensify proliferation and extracellular matrix remodeling in response to mechanical stress. A significant improvement in clinical wound parameters was also observed.

Delayed reconstruction of the combat-related mandibular defects with non-vascularized iliac crest grafts: Defining the optimal conditions for a positive outcome in the retrospective study.

BACKGROUND: Reconstruction of mandibular defects caused by combat injuries is challenging for clinicians due to soft tissue defects and high complication risk. This study evaluated the outcomes of mandibular continuous defects reconstruction with non-vascularized iliac crest graft (NVICG) in patients with combat injuries. MATERIAL AND METHODS: Patients with continuous mandibular defects acquired by high-velocity agents, who received NVICG reconstruction with or without microvascular-free soft tissue or regional flaps, were included in the study. The outcome variable was graft loss due to postoperative complications or full (more than 90 %) resorption. The primary predictor variable was soft tissue defect in the recipient area. The secondary predictor variable was the length of the defect. Variables related to patients, defect site, surgery, and other complications were also evaluated. Statistical analysis was performed with the usage of independent sample t-test, Pearson's chi-squared and Fisher's exact tests with a significance level of P < 0.05 RESULTS: The study included 24 patients with 27 mandibular defects. Overall, the general success rate of reconstructions was 59.3 %. Soft tissue defects were significantly associated with graft failure and other complications (p < 0.05), which were mostly related to soft tissue defects. The graft success rate was only 14.3 % even in minor soft tissue defects. In turn, in reconstructions with sufficient soft tissue coverage, the graft survived in 75.0 % of the cases. In addition, patients with more delayed reconstruction had significantly fewer graft failures than those with earlier surgery (p < 0.05). No associations were found between defect size and complications. CONCLUSION: The sufficient soft tissue coverage is essential in the reconstruction of mandibular defects caused by combat injuries. Also, minor soft tissue defects should be covered with soft tissue flaps to avoid complications and graft loss in these specific injuries. Even large defects can be reconstructed with NIVICG if the soft tissue coverage is sufficient.

Recurrent Adrenergic Stress Provokes Persistent Myocarditis in PD-1-Deficient Mice.

It is unclear how the immune system initiates effective tissue repair responses without also simultaneously activating adaptive immune responses to self-antigens released by damaged or necrotic cells. We studied the role of repetitive adrenergic mediated stress on cardiac injury wild-type and programmed death-1-deficient (PD-1-/-) mice treated with 3 intraperitoneal low doses of isoproterenol followed by an intraperitoneal injection of high-dose ISO 7 days later (ISOprimed/ISOinjury). Repetitive adrenergic stress in ISOprimed/ISOinjury PD-1-/- mice resulted in a persistent dysregulated myocardial inflammatory response characterized by the expansion of autoreactive effector CD8+ T cells, increased cardiac hypertrophy, mild left ventricular dysfunction, and increased lethality when compared with ISOprimed/ISOinjury wild-type mice.

Beyond host defense and tissue injury: the emerging role of neutrophils in tissue repair.

Neutrophils, the most abundant immune cells in human blood, play a fundamental role in host defense against invading pathogens and tissue injury. Neutrophils carry potentially lethal weaponry to the affected site. Inadvertent and perpetual neutrophil activation could lead to nonresolving inflammation and tissue damage, a unifying mechanism of many common diseases. The prevailing view emphasizes the dichotomy of their function, host defense versus tissue damage. However, tissue injury may also persist during neutropenia, which is associated with disease severity and poor outcome. Numerous studies highlight neutrophil phenotypic heterogeneity and functional versatility, indicating that neutrophils play more complex roles than previously thought. Emerging evidence indicates that neutrophils actively orchestrate resolution of inflammation and tissue repair and facilitate return to homeostasis. Thus, neutrophils mobilize multiple mechanisms to limit the inflammatory reaction, assure debris removal, matrix remodeling, cytokine scavenging, macrophage reprogramming, and angiogenesis. In this review, we will summarize the homeostatic and tissue-reparative functions and mechanisms of neutrophils across organs. We will also discuss how the healing power of neutrophils might be harnessed to develop novel resolution and repair-promoting therapies while maintaining their defense functions.

In vivo strain measurements in the human buttock during sitting using MR-based digital volume correlation.

Advancements in systems for prevention and management of pressure ulcers require a more detailed understanding of the complex response of soft tissues to compressive loads. This study aimed at quantifying the progressive deformation of the buttock based on 3D measurements of soft tissue displacements from MR scans of 10 healthy subjects in a semi-recumbent position. Measurements were obtained using digital volume correlation (DVC) and released as a public dataset. A first parametric optimisation of the global registration step aimed at aligning skeletal elements showed acceptable values of Dice coefficient (around 80%). A second parametric optimisation on the deformable registration method showed errors of 0.99mm and 1.78mm against two simulated fields with magnitude 7.30±3.15mm and 19.37±9.58mm, respectively, generated with a finite element model of the buttock under sitting loads. Measurements allowed the quantification of the slide of the gluteus maximus away from the ischial tuberosity (IT, average 13.74 mm) that was only qualitatively identified in the literature, highlighting the importance of the ischial bursa in allowing sliding. Spatial evolution of the maximus shear strain on a path from the IT to the seating interface showed a peak of compression in the fat, close to the interface with the muscle. Obtained peak values were above the proposed damage threshold in the literature. Results in the study showed the complexity of the deformation of the soft tissues in the buttock and the need for further investigations aimed at isolating factors such as tissue geometry, duration and extent of load, sitting posture and tissue properties.

Study on anti-inflammatory effect of Shangkehuangshui in vitro and in vivo based on TLR4/TLR2-NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shangkehuangshui (SK) has been traditionally used to treat traumatic injury, soft tissue and bone injury in Foshan hospital of traditional Chinese medicine for more than 60 years, which composed of many Chinese herbs such as Coptis chinensis Franch., Gardenia jasminoides Ellis, Phellodendron chinense Schneid. and etc. SK exhibits heat-clearing and detoxifying, enhancing blood circulation to eliminate blood stasis properties, and demonstrates noteworthy clinical efficacy. Nevertheless, the underlying mechanism remains uncertain. AIM OF THE STUDY: The early study found that SK had good anti-inflammatory effects in acute soft tissue injury model. This research is to verify the anti-inflammatory properties of SK both in vitro and in vivo via TLR4/TLR2-NF-κB signaling pathway, to clarify the underlying mechanisms responsible for the curative effect of SK. METHODS: The RAW264.7 cells inflammatory model was established with lipopolysaccharide (LPS) in vitro. NO and TNF-α, IL-6, IL-1ß were determined with Griess method and ELISA method respectively. The mRNA and protein expression levels of TLR4/TLR2-NF-κB pathway were evaluated by qPCR and Western blot method. In vivo experiment, chronic soft tissue injury rat models were established by tracking gastrocnemius muscle with electrical stimulation, then local appearance and pathological changes were observed and recorded, the contents of inflammatory factors in serum and tissue were performed. Moreover, we also measured and contrasted the expression of TLR4/TLR2-NF-κB related factors. RESULTS: SK effectively inhibited the LPS-induced generation of inflammatory cytokines, including NO, TNF-α, IL-6 and IL-1ß in RAW264.7 cells, and significantly suppressed the expression of TLR4, TLR2, MyD88, IκB, and NF-κB. In vivo, SK remarkably decreased the damage appearance scores after 4 and 14 days of administration and inhibit the quantity of NO and leukocytes present in the serum. Additionally, the inflammatory infiltration in the pathological section was alleviated, myofibrillar hyperplasia and blood stasis were reduced. SK markedly downregulated NO, TNF-α, IL-6 and IL-1ß in injured tissues of rats, also declined the expression of TLR4, TLR2, MyD88, IκB, NF-κB, IL-6, TNF-α and IL-1ß. CONCLUSION: This study revealed that SK had obvious effects of anti-inflammatory actions in vivo and vitro, effectively reduced acute and chronic soft tissue injury in clinical, this might be attributed to inhibit the TLR4/TLR2-NF-κB pathway, further inhibit the expression of downstream relevant pro-inflammatory cytokines.

Dysfunctional iron metabolism in pressure injuries is related to aberrant CD163 and Homx-1 signal transduction.

Dysregulation of iron metabolism has been associated with impaired chronic wound healing. However, changes in iron metabolism have yet to be reported in pressure injuries, a type of chronic wound. In this study, we aimed to investigate changes in iron metabolism and associated regulatory mechanisms in pressure injuries. We collected tissue biopsies and data from 20 consenting stage IV-pressure injuries patients and 5 non-pressure injuries patients hospitalised at the Affiliated Hospital of Qingdao University between March 2021 and June 2021. In addition, we measured the iron content by inductively coupled plasma mass spectrometry and Prussian blue staining in deep tissue pressure injury mouse models. An Enzyme-linked immune sorbent assay measured the expression of ferritin, ferroportin-1 and transferrin. Immunofluorescence staining, high-throughput transcriptome sequencing, Western blot and RT-qPCR further analysed the fundamental mechanisms regulating iron metabolism. In this study, we observed numerous inflammatory cells infiltrating the marginal tissues of stage IV pressure injury patients and in deep tissue pressure injury models. The expression levels of pro-inflammatory factors, such as inducible nitric oxide synthase and interleukin-6, were significantly increased (p < 0.05). The iron level was proportional to the degree of progression, with the most significant change appearing on the third day in deep tissue pressure injury models (p < 0.05). Enzyme-linked immune sorbent assay results suggested abnormal gene expression was related to iron metabolism, including a substantial increase in ferritin and a significant decrease in the expression of ferroportin-1 (p < 0.05). In addition, immunofluorescence staining and Western blot showed that the expression of macrophage membrane receptor CD163 was abnormally elevated (p < 0.05). Both high-throughput transcriptome sequencing and qRT-PCR results suggested aberrant expression of the CD163/Homx-1-mediated signalling pathway. Dysfunctional iron metabolism was suggested to be related to the aberrant CD163/Homx-1 signalling pathway in deep tissue pressure injury models.

Automated Electrical Stimulation Therapy Accelerates Re-Epithelialization in a Three-Dimensional In Vitro Human Skin Wound Model.

Objective: Electrical Stimulation Therapy (EST) shows promise for the purpose of accelerating wound healing, but the right electrical stimulation parameters and its mode of action remain unclear. We aim to evaluate the effect of a new EST clinical device on epidermal repair using an in vitro human skin wound model. Approach: We scaled up a well-established 3D De-Epidermized Dermis-Human Skin Equivalent (DED-HSE) wound model to fit a clinically used device that delivers preprogrammed microcurrent EST. The impact of EST on re-epithelialization of 4-mm circular epidermal wounds was assessed after 4 and 7 days of treatment, using metabolic activity assay, immunohistochemistry (IHC) staining, and RNA in situ hybridization. Results: EST was successfully applied to the wounded in vitro skin model. Large DED-HSEs retained good cell viability for up to 7 days of EST treatment. Excisional wounds subjected to EST for 4 days consistently exhibited faster closure (mean 65.8%, n = 9) compared to untreated wounds (mean 49.7%, n = 9) (p < 0.05). Wounds exposed to EST exhibited significantly longer epithelial tongues (re-epithelialization mean 50.3%, n = 9) than untreated wounds (mean 26.2%, n = 9) (p < 0.001), suggesting faster keratinocyte migration and proliferation. Increased MMP1 transcription (p < 0.05) in ES-treated periwound suggests a mechanism for enhanced keratinocyte migration. IHC staining showed advanced epidermal proliferation (p63) and differentiation (K10) in EST-exposed wounds (n = 15), as well as stronger attachment of the newly formed epidermis into the dermis compared to untreated controls (n = 15) (p < 0.001). Innovation: We present a novel approach to assess an EST clinical device designed to stimulate wound healing. Using a scaled-up 3D human skin wound model, we could demonstrate the positive effect of EST on epithelial cell responses and shed light on possible mechanism. Conclusion: Our study provides experimental evidence that microcurrent therapy accelerates wound closure and improves the quantity and quality of re-epithelialization.

Tibiotalocalcaneal nail and primary closure for the management of open ankle fractures in the elderly patient; results from a major trauma centre.

INTRODUCTION: Open ankle fractures in elderly patients are challenging injuries to manage. The aim of this study was to assess the outcome of elderly patients with open ankle fractures treated with a tibiotalocalcaneal nail and primary wound closure. METHODS: We identified all open ankle fractures in patients over 65 referred to our major trauma centre managed with a tibiotalocalcaneal nail and primary wound closure over 10 years. We recorded patient demographics, comorbidities, injury mechanism, length of stay, operation, weightbearing status, re-operations, infections and mortality. RESULTS: We included 34 patients with an average age of 87 (73-99). We found 56 % of patients' mobility status declined post-operatively and 21 % of patients were discharged directly home. Four patients required further unplanned surgery including two deep infections requiring amputation. We had a 6 % three month mortality rate. CONCLUSION: Use of a tibiotalocalcaneal nail with primary wound closure offers a reasonable treatment option for open fractures of the ankle in the elderly patient.

Intramedullary Fibular Fixation in One-Stage Ankle Fracture Surgery With Soft Tissue Damage: A Study of 19 Cases.

This study investigates the efficacy of one-stage surgical intramedullary fibular fixation in managing ankle fractures with associated soft tissue damage. Ankle fractures, often encountered, can lead to complications when coupled with soft tissue injury. Traditional plate and screw fixation can exacerbate infection risks and reduce wound healing. To address this, a minimally invasive approach employing intramedullary fixation of the fibula has been proposed. This retrospective analysis, conducted between 2019 and 2021, explores cases of intramedullary fibular fixation for ankle fractures with stage 2-3 soft tissue injuries. A total of 19 patients were included in the study. The procedure involved either ulna intramedullary nails or locking screws. Results indicate that the approach led to successful union (100%), one superficial infection (5.26%), and no complication was observed. While limitations include the retrospective nature and small sample size, this study contributes valuable insights into the use of intramedullary fibular fixation in one-stage surgery for ankle fractures with concurrent soft tissue damage.

Corrigendum: Editorial: MSC-derived exosomes in tissue regeneration.

[This corrects the article DOI: 10.3389/fcell.2023.1293109.].