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Healing diabetic foot ulcers (DFUs) poses a serious challenge for many individuals with diabetes. The use of biomaterials applied locally for treating DFUs has recently garnered significant attention. Here, we present a gel-in-oil nanogel dispersion (G/O-NGD) capable of local delivery of six different growth factors (GFs) via the topical route, followed by an in-vivo evaluation in mice. Both macroscopic and microscopic changes in skin structure were evidented after topical application of GF-cocktail G/O-NGD, and changes in CD68 and CD31 levels and collagen content were measured. Expression and synthesis of Interleukin-6 (IL-6), transforming GF beta 1 (TGF-β1), and basic fibroblast GF (bFGF) were also analyzed. The results showed that a significant reduction in ulcer area, restoration of skin structure, increase in collagen content, angiogenesis, and suppression of inflammation were possible with GF-cocktail G/O-NGD, indicating that G/O-NGD is a prospective carrier for local delivery of GF, improving wound healing processes., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Objective: The study examines the effects of the air-bladder offloading mode of a smart pressure redistribution wheelchair cushion on tissue oxygenation in the gluteal tissue of non-disabled participants. The hypothesis is that the cushion's offloading mode, which involves sequentially deflating its five air-bladders one at a time for a specific duration, would improve tissue oxygenation during sitting., Methods: Two procedures were conducted. The first compared the cushion's offloads to a loaded control (LC) with the cushion on static mode, and the second compared the cushion's offloading mode to a standard manual offload performed by the participant. Three trials of each procedure were performed in randomized order. Tissue oxygenation was continuously monitored with three oxygenation parameters analysed: oxygen saturation (SO 2 ), oxygenated haemoglobin (OxyHb), and deoxygenated haemoglobin (DeoxyHb). Data recordings were segmented in each step of the offloading sequence for analysis. A paired t-test was performed for comparisons with significance considered at α = 0.05. Ten healthy adults participated in the study., Impact: Results showed that as the air bladders deflated over time, the three evaluated parameters changed, affecting oxygenation even when other tissue areas were offloaded. The results indicated that the cushion's sacral offload had the greatest impact on improving tissue oxygenation among the five air-bladders in all ten subjects ( p  < 0.05). Furthermore, SO 2 during the cushion's offload in the sacral region was similar to a manual offload. The study results suggest that the cushion could benefit tissue oxygenation, especially for individuals unable to change positions independently. Further research is needed to determine its effectiveness for wheelchair users.

Introduction: Pressure Injury (PI) is a complex disease process which is influenced by multiple factors, among which ischemia-reperfusion (I/R) injury is closely related to the progression of PI. But its biomarkers are still unclearly. Understanding its physiological mechanisms and related molecular biomarkers is a key to developing effective prevention and therapeutic strategies., Methods: This study through obtained the candidate genes of the differentially expressed genes (DEGs) from the PI rat model by transcriptome sequencing, PI single-cell sequencing database, and genes related to I/R injury from GeneCards database to analyze and screen prognostic related target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) pathway analysis were performed using clusterProfiler package, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The genes related to I/R injury were identified and analyzed using three machine learning algorithms. Then, the hub genes were evaluated using nomogram and receiver operating characteristic (ROC) curves, and validated using immunohistochemistry in the PI rat model., Results: There were finally 7 candidate genes obtained from the intersection of the three datasets. GO and KEGG pathway analysis revealed that the DEGs were enriched in complement and coagulation cascades, and the keratinocyte differentiation is a significant factor. Then, two hub genes Serine protease inhibitor clade E member 1 (SERPINE1) and Cathepsin L (CTSL) were identified through three machine learning algorithms. The two hub genes were indicated had a high prognosis value by nomogram and ROC curves. SERPINE1 and CTSL both play crucial roles in vasculogenesis, coagulation and degradation of the extracellular matrix, which is essential for wound healing. The results of immunohistochemistry demonstrated that SERPINE1 and CTSL are significantly upregulated in skin tissue from PI caused by I/R injury, and their mRNA expression levels significantly correlate with PI outcomes., Conclusion: According to our research we referred that the SERPINE1 and CTSL might be the potential biomarkers of PI., Competing Interests: Declaration of Competing Interest The authors affirm that they do not have any identifiable competing financial interests or personal relationships that might be perceived as influencing the work presented in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Pressure ulcers (PUs) have emerged as a significant burden on both individuals and society. Effective treatment of PUs is a significant clinical challenge due to the compromised tissue microenvironment characterized by extracellular matrix (ECM) depletion, increased levels of reactive oxygen species (ROS), excessive inflammation and impaired angiogenesis. To this end, we have developed a glucomannan hydrogel (GM-P gel ) that mimics the skin's extracellular matrix to accelerate wound healing by regulating chronic inflammation in the PUs. This hydrogel not only faithfully replicates the components and nanofibrous architecture of ECM-like glycoproteins but also exhibits remarkable capabilities in enhancing neovascularization, scavenging ROS, and promoting macrophage polarization toward the M2 phenotype. In summary, this ECM-mimetic multifunctional hydrogel emerges as a promising dressing with diverse functionalities, capable of reshaping the compromised tissue environment without the need for additional drugs, exogenous cytokines, or cells. This presents a compelling and effective strategy for the repair and regeneration of chronic cutaneous wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Slough is a well-known feature of non-healing wounds. This pilot study aims to determine the proteomic and microbiologic components of slough as well as interrogate the associations between wound slough components and wound healing. Ten subjects with slow-to-heal wounds and visible slough were enrolled. Aetiologies included venous stasis ulcers, post-surgical site infections and pressure ulcers. Patient co-morbidities and wound healing outcome at 3-months post-sample collection was recorded. Debrided slough was analysed microscopically, through untargeted proteomics, and high-throughput bacterial 16S-ribosomal gene sequencing. Microscopic imaging revealed wound slough to be amorphous in structure and highly variable. 16S-profiling found slough microbial communities to associate with wound aetiology and location on the body. Across all subjects, slough largely consisted of proteins involved in skin structure and formation, blood-clot formation and immune processes. To predict variables associated with wound healing, protein, microbial and clinical datasets were integrated into a supervised discriminant analysis. This analysis revealed that healing wounds were enriched for proteins involved in skin barrier development and negative regulation of immune responses. While wounds that deteriorated over time started off with a higher baseline Bates-Jensen Wound Assessment Score and were enriched for anaerobic bacterial taxa and chronic inflammatory proteins. To our knowledge, this is the first study to integrate clinical, microbiome, and proteomic data to systematically characterise wound slough and integrate it into a single assessment to predict wound healing outcome. Collectively, our findings underscore how slough components can help identify wounds at risk of continued impaired healing and serves as an underutilised biomarker., (© 2024 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Interleukin-33 (IL-33) is an alarmin released upon epithelial tissue damage. It functions as a nuclear factor for regulating gene expression. We hypothesised that IL-33 is involved in the formation of decubitus ulcers through damaged epidermis. Therefore, this study aimed to clarify the mechanism of IL-33 action in decubitus ulcer formation. IL-33 knockout (KO), soluble stimulation-2 (ST2) transgenic, and wild-type (WT) mice were used to construct an ischemia-reperfusion (I/R) injury as a decubitus model. The ulcer area was significantly reduced in IL-33 KO mice compared to WT mice but was not reduced in ST2 transgenic mice. Anti-IL-33 receptor (transmembrane ST2) antibodies effectively prevented ulcer formation; however, an anti-IL-33 neutralising antibody was ineffective. The number of infiltrating macrophages was higher, while that of neutrophils and mast cells was lower in IL-33 KO mice than in WT mice. The number of M2 macrophages increased in IL-33 KO mice. Characterisation of gene expression levels revealed significantly reduced interleukin-1 beta (IL-1β) and increased C-C motif chemokine ligand 17 expression in IL-33 KO mice. Macrophages isolated from ulcers in WT or IL-33 KO mice stimulated with exogenous IL-33 produced comparable amounts of IL-1β. In conclusion, our study indicates that IL-33 is released in response to I/R injury in the skin, contributing to inflammatory macrophage and mast cell infiltration and stimulation, resulting in IL-1β production and the massive infiltration of effector cells, including neutrophils, which finally induces decubitus ulcer formation. These results suggest that suppressing IL-33 expression could be beneficial for treating early-phase decubitus ulcers., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Pressure ulcer is common in the bedridden elderly with high mortality and lack of effective treatment. In this study, human-adipose-derived-stem-cells-hyaluronic acid gel (hADSCs-HA gel) was developed and applied topically to treat pressure ulcers, of which efficacy and paracrine mechanisms were investigated through in vivo and in vitro experiments., Methods: Pressure ulcers were established on the backs of C57BL/6 mice and treated topically with hADSCs-HA gel, hADSCs, hyaluronic acid, and normal saline respectively. The rate of wound closure was observed continuously during the following 14 days and the wound samples were obtained for Western blot, histopathology, immunohistochemistry, and proteomic analysis. Human dermal fibroblasts (HDFs) and human venous endothelial cells (HUVECs) under normal or hypoxic conditions were treated with conditioned medium of human ADSCs (ADSC-CM), then CCK-8, scratch test, tube formation, and Western blot were conducted to evaluate the paracrine effects of hADSCs and to explore the underlying mechanism., Results: The in vivo data demonstrated that hADSCs-HA gel significantly accelerated the healing of pressure ulcers by enhancing collagen expression, angiogenesis, and skin proliferation. The in vitro data revealed that hADSCs strengthened the proliferation and wound healing capabilities of HDFs and HUVECs, meanwhile promoted collagen secretion and tube formation through paracrine mode. ADSC-CM was also proved to exert protective effects on hypoxic HDFs and HUVECs. Besides, the results of proteomic analysis and Western blot elucidated that lipid metabolism and PPARβ/δ pathway mediated the healing effect of hADSCs-HA gel on pressure ulcers., Conclusion: Our research showed that topical application of hADSCs-HA gel played an important role in dermal regeneration and angiogenesis. Therefore, hADSCs-HA gel exhibited the potential as a novel stem-cell-based therapeutic strategy of treating pressure ulcers in clinical practices., Competing Interests: The authors declare no competing interests in this work., (© 2024 Jin et al.)

This commentary considers the similarities which exist between pressure ulcers (PUs) and diabetic foot ulcers (DFUs). It aims to describe what is known to be shared-both in theory and practice-by these wound types. It goes on to detail the literature surrounding the role of inflammation in both wound types. PUs occur following prolonged exposure to pressure or pressure in conjunction with shear, either due to impaired mobility or medical devices. As a result, inflammation occurs, causing cell damage. While DFUs are not associated with immobility, they are associated with altered mobility occurring as a result of complications of diabetes. The incidence and prevalence of both types of lesions are increased in the presence of multimorbidity. The prediction of either type of ulceration is challenging. Current risk assessment practices are reported to be ineffective at predicting when ulceration will occur. While systemic inflammation is easily measured, the presence of local or subclinical inflammation is harder to discern. In patients at risk of either DFUs or PUs, clinical signs and symptoms of inflammation may be masked, and systemic biomarkers of inflammation may not be elevated sufficiently to predict imminent damage until ulceration appears. The current literature suggests that the use of local biomarkers of inflammation at the skin's surface, namely oedema and temperature, may identify early tissue damage.

Pressure ulcers (PU) are a globally recognised healthcare concern, with their largely preventable development prompting the implementation of targeted preventive strategies. Risk assessment is the first step to planning individualised preventive measures. However, despite the long use of risk assessment, and the >70 risk assessment tools currently available, PUs remain a significant concern. Various technological advancements, including artificial intelligence, subepidermal moisture measurement, cytokine measurement, thermography and ultrasound are emerging as promising tools for PU detection, and subsequent prevention of more serious PU damage. Given the rise in availability of these technologies, this advances the question of whether our current approaches to PU prevention can be enhanced with the use of technology. This article delves into these technologies, suggesting that they could lead healthcare in the right direction, toward optimal assessment and adoption of focused prevention strategies.

The aging process in the elderly results in heightened skin fragility associated with various disorders, including pressure ulcers (PUs). Despite the high incidence of PUs in the elderly population, there is a limited body of research specifically examining the impact of aging on the development of pressure ulcers. Therefore, investigating age-related physiological abnormalities is essential to elucidate the pathogenesis of PUs. Ischemia-reperfusion (I/R) injury and the subsequent oxidative stress caused by reactive oxygen species (ROS) play essential roles in the early stage of PUs. In this study, we used a mouse model of proteasomal dysfunction with an age-related phenotype to examine the role of proteasome activity in cutaneous I/R injury in vivo. Decreased proteasome function did not affect the expression of inflammatory cytokines and adhesion molecules in the I/R area in transgenic mice; however, proteasome inhibition increased oxidative stress that was not attenuated by activation of the oxidative stress response mediated by NF-E2-related factor 2 (Nrf2). In dermal fibroblasts (FCs) subjected to hypoxia-reoxygenation (H/R), proteasome inhibition induced oxidative stress and ROS production, and Nrf2 activation did not adequately upregulate antioxidant enzyme expression, possibly leading to antioxidant/oxidant imbalance. The free radical scavenger edaravone had protective effects against I/R injury in vivo and decreased oxidative stress in FCs treated with a proteasome inhibitor and subjected to H/R in vitro. The results suggest that the age-related decline in proteasome activity promotes cutaneous I/R injury-induced oxidative stress, and free radical scavengers may exert protective effects by preventing oxidative stress in the early stage of PUs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Wound Healing Society.)

Pressure injuries (PI) are debilitating tissue lesions characterised by slow healing and a high risk of severe infection. These injuries result from continued tissue hypoxia, or low tissue oxygen saturation (StO 2 ), which is a consequence of impaired blood circulation caused by continued pressure against tissue. PI result in significant suffering and a substantial financial burden. Therefore, we aim to develop an effective preventive measure. Persons with spinal cord injury (SCI) are at a high risk for PI due to their impaired mobility and lack of sensation to alert them to danger. The aim was to test the feasibility of an alert system based on StO 2 monitoring in persons with SCI using a novel textile-based near-infrared spectroscopy (NIRS) sensor.Sensors consisted of two emission and two detection points, each point comprising eight fibres each with three light-coupling bends. Textile integration of fibres was achieved by stitching on a mass-production stitching machine. Emission fibres were connected to LEDs of 740 nm and 810 nm. Detection fibres were connected to avalanche photodiodes. Sensors were attached to the skin in the high-PI-risk buttocks area covering the bony prominences of the ischial tuberosity. StO 2 was measured in three healthy subjects and two subjects with SCI during repeated sitting and pressure recovery phases.Our experiments showed decreases in StO 2 in both groups during sitting phases: during low-pressure sitting phases, StO 2 decreased on average -0.32%/min in the healthy subjects and at -1.24%/min in the SCI subjects. During high-pressure sitting, these rates increased to -1.16%/min for the healthy subjects and -2.16%/min for the SCI subjects. During recovery phases, StO 2 returned towards normal values, but did not always reach the initial baseline. No discomfort or skin irritation was observed.These first measurements show physiologically reasonable StO 2 values and demonstrate sufficient comfort while sitting on a sensor with no skin irritation or other adverse effects of sitting on the sensor for over 30 min. The nurses involved were satisfied with the easy-of-use, materials used, and patient safety demonstrated during the study. These results show that it is feasible to develop an alert system for PI prevention using a safe, wearable, textile-based NIRS sensor., (© 2024. Oxygen Transport to Tissue International.)

Background: Pressure ulcer is a severe disease in the paralyzed and aging populations. Endothelial progenitor cells (EPCs) are able to regulate ulcer healing by modulating angiogenesis, but the molecular mechanism is still obscure. Sonic hedgehog (SHH) signaling contributes to angiogenesis in various diseases and has been identified to modulate EPCs function. Here, we aimed to explore the significance of SHH signaling in EPCs function during pressure ulcers., Methods: The EPCs were isolated and characterized by the expression of DiI-acLDL and bind fluorescein iso-thiocyanate UEA-1. Cell proliferation was detected by cell counting kit 8 (CCK-8). The DiI-acLDL and bind fluorescein iso-thiocyanate UEA-1 were analyzed by immunofluorescent analysis. The angiogenesis of EPCs was analyzed by tube formation assay. The pressure ulcers rat model was constructed, the wound injury was analyzed by H&E staining and angiogenesis was analyzed by the accumulation of CD31 based on immunofluorescent analysis., Results: The expression of patched-1 and Gli-1 was enhanced by SHH activator SAG but reduced by SHH inhibitor cyclopamine in the EPCsThe PI3K, Akt, eNOS expression and the Akt phosphorylation were induced by SAG, while the treatment of cyclopamine presented a reversed result. The proliferation and migration of EPCs were enhanced by SAG but repressed by cyclopamine or PI3K/AKT/eNOS signaling inhibitor Y294002, in which the co-treatment of Y294002 could reverse the effect of SAG., Conclusions: Thus, we found that SHH signaling activated angiogenesis properties of EPCs to improve pressure ulcers healing by PI3K/AKT/eNOS signaling. SHH signaling may serve as the potential target for attenuating pressure ulcers.

Although the proportion of ulcer patients with medical problems among the elderly has increased with the extension of human life expectancy, treatment efficiency is drastically low, incurring substantial social costs. MSCs have independent regeneration potential, making them useful in clinical trials of difficult-to-treat diseases. In particular, ADMSCs are promising in the stem cell therapy industry as they can be obtained in vast amounts using non-invasive methods. Furthermore, studies are underway to enhance the regeneration potential of ADMSCs using cytokines, growth factors, and gene delivery to generate highly functional ADMSCs. In this study, key regulators of wound healing, SOCS-1, -3, and -5, were combined to maximize the regenerative potential of ADMSCs in pressure ulcer treatments. After transfecting SOCS-1, -3, -5, and SOCS-com into ADMSCs using a non-viral method, the expression of the inflammatory factors TNF-alpha, INF-gamma, and IL-10 was confirmed. ADMSCs transfected with SOCS-com showed decreased overall expression of inflammatory factors and increased expression of anti-inflammatory factors. Based on these results, we implanted ADMSCs transfected with SOCS-com into a pressure ulcer mouse model to observe their subsequent wound-healing effects. Notably, SOCS-com improved wound closure in ulcers, and reconstruction of the epidermis and dermis was observed. The healing mechanism of ADMSCs transfected with SOCS-com was examined by RNA sequencing. Gene analysis results confirmed that expression changes occurred in genes of key regulators of wound healing, such as chemokines, MMP-1, 9, CSF-2, and IL-33, and that such genetic changes enhanced wound healing in ulcers. Based on these results, we demonstrate the potential of ADMSCs transfected with SOCS-com as an ulcer treatment tool.

Pressure ulcers (PUs) are increasing with aging worldwide, but there is no effective causal therapy. Although mesenchymal stem cells (MSCs) promote cutaneous wound healing, the effects of the conditioned medium (CM) of MSCs on cutaneous PU formation induced by ischemia-reperfusion injury have been poorly investigated. To address this issue, herein, we first established an immortalized stem cell line from human exfoliated deciduous teeth (SHED). This cell line was revealed to have superior characteristics in that it grows infinitely and vigorously, and stably and consistently secretes a variety of cytokines. Using the CM obtained from the immortalized SHED cell line, we investigated the therapeutic potential on a cutaneous ischemia-reperfusion mouse model for PU formation using two magnetic plates. This is the first study to show that CM from immortalized SHEDs exerts therapeutic effects on PU formation by promoting angiogenesis and oxidative stress resistance through vascular endothelial growth factor and hepatocyte growth factor. Thus, the CM of MSCs has potent therapeutic effects, whereas these therapies have not been implemented in human medicine. To try to meet the regulatory requirements for manufacturing and quality control as much as possible, it is necessary to produce CM that is consistently safe and effective. The immortalization of stem cells could be one of the breakthroughs to meet the regulatory requirements and consequently open up a novel avenue to create a novel type of cell-free regenerative medicine, although further investigation into the quality control is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Katahira, Murakami, Inoue, Miyakawa, Sakamoto, Furusaka, Watanabe, Sekine, Kuroda, Hasegawa, Mizoguchi and Yoshimoto.)

Pressure ulcer (PU) in patients with diabetes mellitus (DM) is still a clinical intractable issue due to the complicated physiological characteristics by the prolonged high glucose level and impaired angiogenesis. The PU treatment includes surgical debridement, stem cell therapy and growth factors, leading to high cost and repeated professional involvement. Developing effective wound dressing combining the therapeutic cells and growth factors has become highly demanded. Herein, we reported the direct subcutaneous administration of endothelial progenitor cells (EPCs) and acid fibroblast growth factor (aFGF) with a shape-memorable methacrylated gelatin cryogel (EPCs/aFGF@GelMA) for the therapy of PU in rats with DM. This EPCs/aFGF@GelMA cryogel system presented microporous structure, elastic mechanical strength and enhanced cell migration property with controlled release of aFGF. Moreover, compared with EPCs/aFGF and GelMA alone, in vivo results showed that this EPCs/aFGF@GelMA system exhibited accelerated wound closure rate, enhanced granulation formation, collagen deposition as well as re-epithelization. Importantly, we found that the excellent positive performance of EPCs/aFGF@GelMA is due to its up-regulation of HIF-ɑ upon the wound site, modulating the microenvironment of wound site to initiate the impaired local angiogenesis. Collectively, this hybrid gelatin cryogels show great promise for biomedical applications, especially in tissue engineering and regenerative medicine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pressure ulcers are preventable, yet highly prevalent, chronic wounds that have significant patient morbidity and high healthcare costs. Like other chronic wounds, they are characterized by impaired wound healing due to dysregulated immune processes. This review will highlight key biochemical pathways in the pathogenesis of pressure injury and how this signaling leads to impaired wound healing. This review is the first to comprehensively describe the current literature on microRNA (miRNA, miR) regulation of pressure ulcer pathophysiology.

Background: CircZNF609 (cZNF609) is previously revealed as an essential mediator in oxidative stress. This paper determined the role of cZNF609 in skin oxidative damage to evaluate its importance in pressure ulcer. Methods: HaCaT cells treated by H 2 O 2 were considered as a cell model of pressure ulcer. The role of cZNF609 in the model was checked by conducting CCK-8 assay, FITC-PI double-staining, ROS detection and Western blot. The downstream gene and signalling of cZNF609 were studied by utilizing qRT-PCR and Western blot. Results: HaCaT cells were remarkably damaged by H 2 O 2 , as evidenced by the viability loss, apoptosis and ROS generation. It was coupled with the elevated expression of p53, p16, Bax and the activated forms of caspase-3 and PARP. Meanwhile, cZNF609 was high-expressed in response to H 2 O 2 . The oxidative stress driven by H 2 O 2 was alleviated by transfection with cZNF609 specific siRNA. Further, the anti-antioxidant impacts of cZNF609 silence were impeded by miR-145 silence. The inhibition of JNK and p38MAPK pathways induced by cZNF609 silence was impeded by miR-145 silence. Conclusion: The protective function of cZNF609 silence in H 2 O 2 -injured HaCaT cells was revealed in vitro . Silence of cZNF609 exhibited its impact possibly through regulating miR-145, and JNK and p38MAPK pathways.

Study Design: Secondary analysis of a cross-sectional observation study., Objectives: To determine the relationship between skin ultrasound images and muscle damage in wheelchair basketball athletes, using skin blotting examinations of the ischial regions., Setting: Community, Japan., Methods: Fourteen elite wheelchair basketball athletes were recruited. We obtained data regarding participants' characteristics. We undertook ultrasonographic images and quantitative skin blotting of the ischial region before and after training, and after rest., Results: We identified Category II and III pressure injuries in 2 of the 12 participants. Structural features were classified into four categories based on ultrasonographic features, namely, normal skin structure, unclear superficial and deep fascia, cloudy fat layer, and fat infiltration and low-echoic lesion/anechoic lesions. The muscle-type creatinine kinase (CK-M) level (median [interquartile range: IQR], 2.98 [2.80-3.47]) in the fat infiltration and low-echoic lesion/anechoic lesion group was significantly higher (1.43 [1.41-1.49]) than in a nonfat infiltration and low-echoic lesion/anechoic lesion group after training (p = 0.03). The interleukin-6 (IL-6) level (median [IQR], 23.5 [16.15-58.97]) in the fat infiltration and low-echoic lesion/anechoic lesion group was significantly higher (1.94 [1.74-4.44]) than in the nonfat infiltration and low-echoic lesion/anechoic lesion group after rest (mean difference = -25.4, 95% CI -61.1 to 10.7, p = 0.03)., Conclusions: The combination of ultrasonographic images and skin blotting using CK-M and IL-6, could detect early deep tissue damage in wheelchair athletes. These techniques could be potentially useful in the treatment and prevention of pressure injuries., Sponsorship: This study was supported in part by YAMAHA Motor Foundation for Sports.

Objective: Inflammation triggered by tissue injury increases blood flow to the injured area, resulting in fluid accumulation below the epidermis known as subepidermal moisture (SEM). This accumulation can be assessed using an SEM scanner. The primary aim of this study was to determine whether levels of SEM from repeated measures at a localized area confirm the absence of a pressure injury at that site in healthy participants., Methods: Fifty patients attending a specialized pain clinic who were at very low risk of or unaffected by pressure injuries were enrolled. Subepidermal moisture readings were gathered at the center and near-proximate to the bony prominences of the heel and sacrum., Main Results: Among the participants, repeated localized measurements did not differ significantly at or around a single anatomic site. The heel had a slightly higher variation than the sacrum, although the variance was less than 0.6 SEM units, indicating that there is likely no inflammation at these sites in patients who are not at risk of pressure injuries and who show no visual signs of localized tissue inflammation. Demographic and other potential confounder data were gathered, but no statistically significant findings emerged from these data., Conclusions: The relatively flat pattern of SEM values around the bony prominences of the heels and sacrum in healthy participants supports the hypothesis that healthy tissue is not inflamed.

Pressure ulcers (PUs) are a common clinical issue lacking effective treatment and validated pharmacological therapy in hospital settings. Ischemia-reperfusion injury of deep tissue, especially muscle, plays a vital role in the formation and development of the overwhelming majority of PUs. However, muscular protein expression study in PUs has not been reported. Herein, we aimed to investigate the muscular proteins profiles in PUs and to explore the pathological mechanism of PUs. The iTRAQ LC-MS/MS was conducted to detect the protein profiles in clinical muscle samples of PUs. The GO and KEGG pathways analyses were performed for annotation of differentially expressed proteins. Protein-protein interaction (PPI) network was constructed by STRING online database, and hub proteins were validated by the immunoblotting. Based on proteomics results, we found a number of proteins that were differentially expressed in PU muscle samples compared with the normal and identified unique proteins expression patterns between these two groups, suggesting that they might involve in pathological process of the disease. Importantly, cathepsin B and D, as well as other autophagy-lysosome and apoptosis associated proteins were identified. Further experiments characterize the expression of these proteins and their regulation in the process of apoptosis and autophagy. These findings may provide novel insights into the mechanisms of lysosome-associated pathways involved in the initiation of PUs. This is the first study linking proteomics to PUs muscle tissues, which indicated cathepsin B and D might be key drug target for PUs., (© 2020 The Author(s).)

Objective: Severe pressure ulcers (PUs) do not respond to conservative wound therapy and need surgical repair. To better understand the pathogenesis and to advance on new therapeutic options, we focused on the proteomic analysis of PU, which offers substantial opportunities to identify significant changes in protein abundance during the course of PU formation in an unbiased manner. Approach: To better define the protein pattern of this pathology, we performed a proteomic approach in which we compare severe PU tissue from spinal cord injury (SCI) patients with control tissue from the same patients. Results: We found 76 proteins with difference in abundance. Of these, 10 proteins were verified as proteins that define the pathology: antithrombin-III, alpha-1-antitrypsin, kininogen-1, alpha-2-macroglobulin, fibronectin, apolipoprotein A-I, collagen alpha-1 (XII) chain, haptoglobin, apolipoprotein B-100, and complement factor B. Innovation: This is the first study to analyze differential abundance protein of PU tissue from SCI patients using high-throughput protein identification and quantification by tandem mass tags followed by liquid chromatography tandem mass spectrometry. Conclusion: Differential abundance proteins are mainly involved in tissue regeneration. These proteins might be considered as future therapeutic options to enhance the physiological response and permit cellular repair of damaged tissue., Competing Interests: No competing financial interests exist. The authors listed expressly wrote the content of this article. No ghost writers were used to write this article., (© Montserrat Baldan-Martin, et al. 2020; Published by Mary Ann Liebert, Inc.)

Background: Diabetes mellitus is a growing global health issue nearly across the world. Diabetic patients who are prone to develop diabetes-related complications often exhibit progressive neuropathy (painless and sensory loss). It is usual for small wounds to progress to ulceration, which especially worsens with peripheral arterial disease and in the presence of anaerobic bacteria, culminating into gangrene. In our study, vaccarin (VAC), the main active monomer extracted from Chinese herb vaccariae semen , is proven to have a role in promoting diabetic chronic wound healing through a cytoprotective role under high glucose conditions., Materials and Methods: We constructed a pressure ulcer on both VAC-treated and control mice based on a type 1 diabetes (T1DM) model. The wound healing index was evaluated by an experimental wound assessment tool (EWAT). We also determined the effect of VAC on the proliferation and cell migration of human microvascular endothelial cells (HMEC-1) by a cell counting kit (CCK-8), a scratch and transwell assay., Results: The results demonstrated that VAC could promote the proliferation and migration of high glucose-stimulated HMEC-1 cells, which depend on the activation of FOXP2/AGGF1. Activation of the angiogenic factor with G patch and FHA domains 1 (AGGF1) caused enhanced phosphorylation of serine/threonine kinase (Akt) and extracellular regulated protein kinases (Erk1/2). By silencing the expression of forkhead box p2 (FOXP2) protein by siRNA, both mRNA and protein expression of AGGF1 were downregulated, leading to a decreased proliferation and migration of HMEC-1 cells. In addition, a diabetic chronic wound model in vivo unveiled that VAC had a positive effect on chronic wound healing, which involved the activation of the above-mentioned pathways., Conclusions: In summary, our study found that VAC promoted chronic wound healing in T1DM mice by activating the FOXP2/AGGF1 pathway, indicating that VAC may be a promising candidate for the treatment of the chronic wounds of diabetic patients.

The development of pressure ulcers is associated with four different pathways: ischemia, ischemia-reperfusion injury, impaired interstitial fluid flow and lymphatic drainage, and cell deformation. For prediction of pressure ulcer development, it is important to detect the tissue response involved in the pathways at the molecular level. However, non-invasive techniques for detecting this tissue response are not available. This study aimed to demonstrate that the secretion of the candidate marker proteins in pressure-loaded mouse skin can be detected by skin blotting, and to propose a novel direct skin assessment method for predicting pressure ulcer development. We created three different tissue damage models: early stage pressure ulcers, blanchable erythema and intact skin. We confirmed the pathways involved in the pressure ulcer development by histological analyses in the pressure ulcer model. Interleukin-1α (IL-1α), vascular endothelial growth factor C (VEGF-C) and heat shock protein 90α (HSP90α) were expressed in the pressure ulcer model at a significantly different level compared to the blanchable erythema or intact skin during the time course. Detecting the secretion of these novel biomarkers by skin blotting can be a useful method for non-invasive prediction of pressure ulcer development., Competing Interests: Declaration of competing interest The authors hold a US patent US62/278,454., (Copyright © 2019 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

In our previous study, we proposed an animal model in which pressure ulcer-like dermal lesions can be produced by denervation of the sciatic nerve and application of a pressure load to rat heel skin. In the present study, we divided these animals into non-treated and pressure loading groups, and initiated hindlimb unloading (depressurization) by tail suspension at 1, 3, 5, 7, and 14 days after inflicting lesions (1-14d pressurization groups). Chronological changes in heel lesions were examined morphologically in all treatment groups after 1, 3, 7, 14, 28, and 40 days. Open dermal lesions were formed by 14 days in the loading group and numerous macrophages were present. In the 14d pressurization group, numerous macrophages were still distributed in and around lesions and Vascular endothelial cell growth factor (VEGF) expression was strongly detected by 3 days, but a thin germinal layer began to appear and CD68-positive macrophages and VEGF immunoreactions decreased gradually by 7 days later. By 14 days after depressurization, the germinal layer was repaired, and macrophages and immunoreactions of VEGF were similar to those of non-treated skin. These chronological changes were similar to those in human pressure ulcers, but from 5d after depressurization, different chronological changes were observed. Specifically, epidermis was thickened and macrophages were hardly detected at 5 days in the loading group, but the epidermis disappeared by 1 day in the 5d pressurization group. Subsequently, numerous macrophages aggregated and VEGF expression was increased by 3 days, and the remaining healing process was similar to that in the 14d pressurization group. Even when unloading was performed during the early stages (5d pressurization group), the epidermis disappeared and macrophages were then distributed before repair of the lesion was observed. These results suggest that earlier migration of macrophages to skin lesions might be associated with rapid wound healing., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Pressure ulcers (PUs) represent a substantial burden to both patients and healthcare providers. Accordingly, effective prevention strategies should follow early detection of PUs. Anaerobic metabolites, such as lactate and pyruvate, are promising noninvasive biomarkers indicative of tissue ischaemia, one of the major mechanisms leading to PU development. The aim of this study was to investigate if the temporal release profile of these metabolites in sweat and sebum is sensitive to detect local tissue changes resulting from prolonged mechanical loads. The sacrum of healthy volunteers was subjected to two different loading protocols. After a baseline measurement, the left and right side of the sacrum were subjected to continuous and intermittent loading regimen, respectively, at a pressure of 100 mmHg. Biomarker samples were collected every 20 min, with a total experimental time of 140 min. Sweat was collected at 37 ∘ C and 80% relative humidity, and sebum at ambient conditions, from 11 to 13 volunteers, respectively. Both samples were analysed for lactate and pyruvate concentrations using ultra-high performance supercritical fluid chromatography mass spectrometry. Prior to analysis metabolite concentrations were normalized to individual baseline levels and, in the case of sweat, additional normalization was performed to an unloaded control site to account for fatigue of sweat glands. Although substantial variability was present, the temporal release profiles of both sweat and sebum metabolites reflected the applied loading regimen with increased levels upon load application, and recovery to baseline levels following load removal. Highest relative increases were 20% and 30% for sweat lactate and pyruvate, respectively, and 41% for sebum lactate. Sebum pyruvate was not present in quantifiable amounts. There was a linear correlation between the individual responses to intermittent and continuous loading. The present study revealed that metabolite biomarkers in both sweat and sebum were sensitive to the application of mechanical loads, indicative of local ischaemia within skin and soft tissues. Similar trends in metabolic biomarkers were observed in response to intermittent and continuous loading regimens in both sweat and sebum. Metabolites represent a potential means to monitor the health of loaded skin and soft tissues informing timely interventions of PU prevention., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To explore the expression levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein and the change of MMP-9/TIMP-1 ratio in wound exudates of patients with stages Ⅲ and Ⅳ pressure ulcers during wound healing. Methods: From July 2017 to July 2018, 30 patients with stage Ⅲ pressure ulcers [30 wounds, 16 males and 14 females, aged (65±10) years] and 34 patients with stage Ⅳ pressure ulcers [50 wounds, 17 males and 17 females, aged (65±9) years] admitted to Hebei General Hospital who met the inclusion criteria were enrolled in this prospective cohort study. According to the principle of wound treatment and the characteristics and needs of wound in different periods, individualized intervention measures were formulated for patients and appropriate dressings were selected. At the time of admission and on 7, 14, 21, 28 days of treatment, the healing of pressure ulcer wounds was evaluated by Pressure Ulcer Healing Scale. Afterwards, the wound exudate was collected at each time point to detect the expression levels of MMP-9 and TIMP-1 protein by enzyme-linked immunosorbent assay, and the MMP-9/TIMP-1 ratio was calculated. Data were processed with analysis of variance for repeated measurements of single group and linear trend test. Results: (1) There were significantly statistical differences in wound healing scores of patients with stages Ⅲ and Ⅳ pressure ulcers among the time of admission and on 7, 14, 21, 28 days of treatment within each stage ( F =145.382, 153.234, P <0.01), and they all showed a gradually decreasing trend ( F =170.466, 284.585, P <0.01). (2) At the time of admission and on 7, 14, 21, 28 days of treatment, the expression levels of MMP-9 protein in wound exudates of patients with stages Ⅲ and Ⅳ pressure ulcers were (171±104), (138±88), (110±70), (85±55), (62±41) ng/L and (193±107), (173±104), (139±83), (114±70), (89±56) ng/L, respectively. There were significantly statistical differences within each stage ( F =58.007, 111.680, P <0.01), and they all showed a gradually decreasing trend ( F =62.901, 134.628, P <0.01). At the time of admission and on 7, 14, 21, 28 days of treatment, the expression levels of TIMP-1 protein in wound exudates of patients with stages Ⅲ and Ⅳ pressure ulcers were (6.2±3.9), (5.6±3.4), (5.1±3.1), (4.4±2.5), (3.8±2.3) ng/L and (4.8±2.5), (4.7±2.6), (4.4±2.6), (4.6±2.7), (4.1±2.4) ng/L, respectively. There were significantly statistical differences within each stage ( F =25.479, 7.778, P <0.01), and there was a gradually decreasing trend in stage Ⅲ ( F =62.901, P <0.01) and a decreasing trend in stage Ⅳ ( F =134.628, P <0.01). At the time of admission, the expression levels of MMP-9 and TIMP-1 in wound exudates of patients with stage Ⅲ pressure ulcers were similar to those of patients with stage Ⅳ pressure ulcers ( t =-1.03, 1.47, P >0.05). (3) At the time of admission and on 7, 14, 21, 28 days of treatment, the MMP-9/TIMP-1 ratios in the wound exudates of patients with pressure ulcers of stages Ⅲ and Ⅳ were 30±13, 25±9, 22±9, 20±8, 17±6 and 43±19, 37±13, 32±10, 26±9, 22±9, respectively. There were significantly statistical differences within each stage ( F =37.173, 97.191, P <0.01), and they all showed a gradually decreasing trend ( F =54.183, 130.088, P <0.01). At the time of admission, the MMP-9/TIMP-1 ratio in wound exudates of patients with stage Ⅳ pressure ulcers was significantly higher than that of patients with stage Ⅲ pressure ulcers ( t =-3.42, P <0.01). Conclusions: During the wound healing process of patients with stages Ⅲ and Ⅳ pressure ulcers, the expression levels of MMP-9 and TIMP-1 protein and the MMP-9/TIMP-1 ratio in wound exudates show a decreasing trend. The stage of wound healing can be predicted according to the expression level of MMP-9 protein and the MMP-9/TIMP-1 ratio.

Objective: This study aimed to examine the superiority of peroxidase detection of macroscopic observations using rat wounds, and to test the external validity of the peroxidase analysis in pressure ulcers (PU) in humans., Method: In the animal study, rat wounds were analysed. A cross-sectional study analysed, by wound blotting, exudate samples from full-thickness PUs. Peroxidase activity was divided into two groups (ring and non-ring signals). Scores in the 'inflammation/infection' and 'necrotic tissue' components of DESIGN, a classification tool of PUs, were compared between the groups., Results: In the animal study, 20 rat wounds were assessed and in the clinical study, 62 samples were collected from 26 full-thickness PUs of 21 patients aged ≥ 65 years. In the animal study, five of six wounds with clinical inflammation signs showed ring signal (defined as a signal on the wound edge and no signal on the wound bed). While the tissue sections of three wounds with a ring signal showed inflammatory features, they showed no clinical signs of 'inflammation/infection'. In the clinical study, which analysed 630 ring and 32 non-ring signals, 13 samples in the ring signal group and five in the non-ring signal group had 'inflammation/infection; scores of ≥1 (p=0.016). Despite having no clinical signs, 17 samples showed the ring signal., Conclusion: This study revealed the external validity of the wound blotting analysis of peroxidase and demonstrated its use to detect subclinical inflammation.

Background: Pressure ulcers (PU) are serious medical problems that involve several factors. Recent studies suggest that oxidative stress along with chronic inflammation may cause and develop PU. However, the metabolic disturbances underlying PU are not totally known. The purpose of this study is to evaluate biochemical oxidative stress markers in Tunisian patients suffering from PU. Methods: A total of 100 adult patients with PU and 213 healthy adult controls were selected for the study. Biochemical parameters related to immune profiles, and biomarkers of the liver, kidney, and inflammatory proteins were evaluated using recently developed automated measurement methods. Oxidant-antioxidant system markers (malondialdehyde (MDA), carbonyl proteins, total antioxidant potential, total oxidant status (TOS), catalase, and glutathione-S-transferase) were studied using appropriate methods. Results: Patients with PU showed, remarkably, abnormal levels of biochemical markers and relatively higher systemic oxidative stress compared to healthy subjects. This provides the first evidence that alterations in biochemical parameters and oxidative stress are features of PU. Conclusions: Understanding the signaling pathways involved in the development of PU will provide experts with additional knowledge for therapeutic strategies aimed at limiting the oxidative and inflammatory reactions in affected patients. ClinicalTrials.gov ID: NCT0257800.

Objective: To analyze the expression and relationship of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR) in local skin tissues of pressure injury and investigate the possible mechanism of stage 3 pressure injury refractory wound., Methods: Forty male SD rats were randomly divided into normal control group, compressed 3 d, 5 d, 7 d, and 9 d groups. Stage 3 pressure injury animal model were established by magnet compression. The morphology of skin was observed by HE staining. The expression of VEGF was detected by immunohistochemistry. The expression levels of HIF-1α, VEGF and KDR protein in skin tissue were detected by Western blot. One-way analysis of variance and LSD test were performed on the data., Results: ①The HE results showed that compared with the normal control group, the epidermis of the compressed group was gradually thickened, the number of blood vessels was decreased, the collagen arrangement disordered and inflammatory cells infiltration were increased. ②Immunohistochemical results showed that the expression of VEGF protein in the 3 d group was significantly higher than that in the normal control group (P＜0.01). The expression of VEGF protein in the skin tissue of 5 d, 7 d and 9 d groups was lower than that in normal control group (P＜0.05). WB results were consistent with immunohistochemistry results. ③WB results showed that the expression of HIF-1α in the skin tissues of the rats in 3 d, 5 d and 7 d groups was higher than that in the normal control group (P＜0.01 or P＜0.05). The expression of KDR protein was lower than that of the normal control group (P＜0.05 or P＜0.01)., Conclusion: HIF-1α mediated reduction of VEGF and KDR protein expression and decreased tissue angiogenesis may be one of the important causes of chronic dysfunction of stage 3 pressure injury.

The prevention of progression of Category I pressure ulcers (PUs) to Category II or higher is important, as Category II or higher PUs are open wounds and have a higher infection risk. Prognosis prediction of Category I PUs is necessary to provide successful intensive care for PUs with impaired healing. We focused on skin blotting using plasminogen activator inhibitor 1 (PAI1), interleukin-1α (IL-1α), vascular endothelial growth factor C (VEGF-C), and heat shock protein 90α (HSP90α). This pilot study was conducted at long-term-care and general hospitals to examine the applicability of DESIGN-R and thermography; the feasibility of skin blotting technique; the biomarker candidates, PAI1, IL-1α, VEGF-C, and HSP90α; and sample size for prognosis prediction for Category I PUs. Patients aged >65 years underwent skin blotting, scoring for DESIGN-R, and took thermography images of their Category I PU site. Albumin signals were not detected in one out of three participants. PAI1, IL-1α, VEGF-C, and HSP90α were detected in 19 participants, among whom 11 participants could be followed up after one week. There was no difference in DESIGN-R score and skin surface temperature between normal and impaired healing groups, and the sample size was calculated as 16. In conclusion, the feasibility of skin blotting was confirmed. PAI1, IL-1α, VEGF-C, and HSP90α could be biomarker candidates for prognosis prediction for Category I PU and the combination of VEGF-C and HSP90α could be associated with the prognosis of Category I PU. We need to investigate 842 patients in a future study., (Copyright © 2019. Published by Elsevier Ltd.)

Pressure-induced deep tissue injury is a form of pressure ulcer which is difficult to detect and diagnose at an early stage, before the wound has severely progressed and becomes visible at the skin surface. At the present time, no such detection technique is available. To test the hypothesis that muscle damage biomarkers can be indicative of the development of deep tissue injury after sustained mechanical loading, an indentation test was performed for 2 h on the tibialis anterior muscle of rats. Myoglobin and troponin were analysed in blood plasma and urine over a period of 5 days. The damage as detected by the biomarkers was compared to damage as observed with T 2 MRI to validate the response. We found that myoglobin and troponin levels in blood increased due to the damage. Myoglobin was also increased in urine. The amount of damage observed with MRI immediately after loading had a strong correlation with the maximal biomarker levels: troponin in blood r s = 0.94; myoglobin in blood r s = 0.75; and myoglobin in urine r s = 0.57. This study suggests that muscle damage markers measured in blood and urine could serve as early diagnosis for pressure induced deep tissue injury., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To compare the tissue morphology and gene expressions of inflammatory and repair-related factors in chronic refractory wound tissue including pressure ulcers and diabetic feet. Methods: During August 2016 to September 2017, 10 samples of prepuce were collected after circumcision of 10 urological patients [all male, aged (38±4) years old] admitted in the First Affiliated Hospital of Nanchang University and included in normal skin group, samples of tissue around the edge of wounds with blood supply were collected from 9 heat or electric burn patients [6 male patients, 3 female patients, aged (51±8) years old], 13 pressure ulcer patients [9 male patients, 4 female patients, aged (51±14) years old] and 10 diabetic foot patients [8 male patients, 2 female patients, aged (61±10) years old] during the operations. The samples were divided into burn wound group (9 samples), pressure ulcer group (13 samples), and diabetic foot group (10 samples). Ten slices were taken from pressure ulcer group and diabetic foot group respectively, and 5 slices in each group were used to observe the tissue morphology and expressions of Ki67 and CD31 of wounds respectively with immunofluorescence method. Ten samples from normal skin group, 9 samples from burn wound group, 13 samples from pressure ulcer group, and 10 samples from diabetic foot group were collected for analysis of mRNA expressions of vascular endothelial growth factor 192 (VEGF192), transforming growth factor β (TGF-β), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) , interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) by real time fluorescent quantitative reverse transcription polymerase chain reaction. Data were processed with Mann-Whitney U test and Kruskal-Wallis rank-sum test. Results: (1) The expression level of Ki67 in diabetic foot group (390±100) was higher than that of pressure ulcer group (182±14, Z =-2.611, P <0.01). (2) Although there were a large number of vascular endothelial cells (CD31 positive cells) in wounds of diabetic foot group, their distribution was disordered and failed to form intact lumen. There were less vascular endothelial cells in wounds of pressure ulcer group than those of diabetic foot group, but the complete lumen was formed. (3) The mRNA expression levels of VEGF192 in wounds of burn wound group, pressure ulcer group, and diabetic foot group were significantly lower than the level in normal skin group ( H =13.72, 30.50, 15.20, P <0.05 or P <0.01), and the level was the lowest in pressure ulcer group. The mRNA expression level of VEGF192 in wounds of pressure ulcer group was significantly lower than that of diabetic foot group ( H =15.30, P <0.01). Compared with that of normal skin group, the mRNA expression level of TGF-β in wounds of burn wound group showed no significant difference ( H =-9.50, P >0.05), while the mRNA expression levels of TGF-β in wounds of pressure ulcer group and diabetic foot group were significantly decreased ( H =18.04, 14.50, P <0.01). The mRNA expression level of TGF-β in wounds of pressure ulcer group was similar to that of diabetic foot group ( H =3.54, P >0.05). (4) Compared with those of normal skin group, the mRNA expression levels of VCAM-1 in wounds of burn wound group and pressure ulcer group were significantly increased ( H =-22.50, -11.50, P <0.05 or P <0.01), and there was no significant difference in the mRNA expression level of VCAM-1 in wounds of diabetic foot group ( H =10.00, P >0.05); the mRNA expression level of ICAM-1 in wounds of burn wound group showed no significant difference ( H =-9.50, P >0.05), and the levels of ICAM-1 in wounds of pressure ulcer group and diabetic foot group were significantly decreased ( H =16.50, 16.50, P <0.01). The mRNA expression level of VCAM-1 in wounds of pressure ulcer group was significantly higher than that of diabetic foot group ( H =-21.50, P <0.01), the mRNA expression level of ICAM-1 in wounds of pressure ulcer group was similar to that of diabetic foot group ( H =0, P >0.05). (5) Compared with those of normal skin group, except for the mRNA expression level of IL-1β in wounds of diabetic foot group showed no significant difference ( H =-10.00, P >0.05), the mRNA expression levels of IL-1β in wounds of burn wound group and pressure ulcer group were significantly increased ( H =-32.50, -21.50, P <0.01); the mRNA expression levels of IL-6 were significantly increased in wounds of burn wound group, pressure ulcer group, and diabetic foot group ( H =-17.50, -30.50, -11.80, P <0.05 or P <0.01); except for the mRNA expression level of TNF-α in wounds of burn wound group showed no significant difference ( H =-9.50, P >0.05), the mRNA expression levels of TNF-α in wounds of pressure ulcer group and diabetic foot group were significantly decreased ( H =18.04, 14.50, P <0.01). The mRNA expression levels of IL-1β and TNF-α in wounds of pressure ulcer group were significantly lower than those of burn wound group ( H =11.00, 27.54, P <0.05 or P <0.01), while the mRNA expression level of IL-6 was significantly higher ( H =-13.00, P <0.05). The mRNA expression levels of IL-1β and TNF-α in wounds of diabetic foot group were significantly lower than those of burn wound group ( H =22.50, 24.00, P <0.01), while the mRNA expression level of IL-6 showed no significant difference ( H =5.70, P >0.05). Conclusions: The phenotypes of diabetic foot and pressure ulcer vary from the expressions levels of proliferating cell nuclear antigen and blood vessels forming ability to the expression levels of growth factors, cell adhesion factors, and inflammatory cytokines.

Despite advances in regenerative medicine and tissue engineering, human skin substitutes remain a clear goal to achieve. Autografts remain the principal clinical option. The long-term changes in dermis, as well as its response after injuries, are not well known. Research in this field has been hindered by a lack of experimental animal models. This study analyzes the architectural dermal scaffold (collagen and elastin fibers plus fibrillin-microfibrils) changes in a model of human skin pressure ulcers in mice. Immunosuppressed NOD/Scid mice (n=10) were engrafted with human skin of dimensions 4x3 cm. After 60 days as a permanent graft, a pressure ulcer (PU) was created in the human skin using a compression device. Three study groups were established: full-thickness skin graft before (hFTSG) and after applying mechanical pressure (hFTSG-PU). Native human skin was used as control group. Evaluations were conducted with visual and histological assessment. Scaffold components from each group were compared by immunohistochemical staining (tropoelastin, collagen I and III, metalloproteins (MMP), fibulins, and lysil oxidases (LOX) among others). The long-term engrafted skin showed a certain degradative state of dermis scaffold, as noticed by the active expression of MMPs and tropoelastin compared to native skin. However, a great reparative response after pressure ulcer onto the engrafted skin was observed. A significant increase of fibrillin microfibrils components (TGF-β, MAGP-1 and fibrillin-1), and matrix suprastructures of collagen I, III and LOX lead to an active restructuration of dermal tissue. Our human skin model in mice revealed the important role of the dermal scaffold component to reach skin stability and its capability to react to mechanical pressure injuries. These results showed the important role of dermal scaffold to support the histoarchitecture and mechanosensation of the human skin.

Pressure ulcer formation depends on various factors among which repetitive ischaemia/reperfusion(I/R) injury plays a vital role. Molecular hydrogen (H 2 ) was reported to have protective effects on I/R injuries of various internal organs. In this study, we investigated the effects of H 2 inhalation on pressure ulcer and the underlying mechanisms. H 2 inhalation significantly reduced wound area, 8-oxo-dG level (oxidative DNA damage) and cell apoptosis rates in skin lesions. H 2 remarkably decreased ROS accumulation and enhanced antioxidant enzymes activities by up-regulating expression of Nrf2 and its downstream components in wound tissue and/or H 2 O 2 -treated endothelia. Meanwhile, H 2 inhibited the overexpression of MCP-1, E-selectin, P-selectin and ICAM-1 in oxidant-induced endothelia and reduced inflammatory cells infiltration and proinflammatory cytokines (TNF-α, IL-1, IL-6 and IL-8) production in the wound. Furthermore, H 2 promoted the expression of pro-healing factors (IL-22, TGF-β, VEGF and IGF1) and inhibited the production of MMP9 in wound tissue in parallel with acceleration of cutaneous collagen synthesis. Taken together, these data indicated that H 2 inhalation suppressed the formation of pressure ulcer in a mouse model. Molecular hydrogen has potentials as a novel and alternative therapy for severe pressure ulcer. The therapeutic effects of molecular hydrogen might be related to its antioxidant, anti-inflammatory, pro-healing actions., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: To evaluate the effect of laser irradiation at different wavelengths on the expression of selected growth factors and inflammatory mediators at particular stages of the wound healing process. Methods: Sixty-seven patients were recruited, treated, and analyzed (group A - 940 nm: 17 patients; group B - 808 nm: 18 patients; group C - 658 nm: 16 patients; group D - sham therapy: 17 patients). Patients received a basic treatment, including repositioning and mobilization, air pressure mattress and bed support surfaces, wound cleansing and drug therapy. Additionally, patients received laser therapy once a day, 5 times a week for 1 month in use of a semiconductor lasers (GaAlAs) which emitted a continuous radiation emission at separate wavelengths of 940 nm (group A), 808 nm (group B) and 658 nm (group C). In group D (sham therapy), laser therapy was applied in the same manner, but the device was off during each session (only the applicator was switched on to scan pressure ulcers using none coherent red visible light). Results: The positive changes in the measured serum (IL-2, IL-6 and TNF-α) and wound tissue (TNF-α, VEGF and TGFβ1) parameters appeared to be connected only with the wavelength of 658 nm. The significant change in pro-inflammatory mediator levels [interleukin 2 (IL-2) with p=0.008 and interleukin 6 (IL-6) with p=0.016] was noticed after two weeks of laser therapy. In the other groups, the inflammation was also reduced, but the process was not as marked as in group C. Similarly, in the case of tumor necrosis factor (TNF-α) concentration, where after two weeks of treatment with irradiation at a wavelength of 658 nm, a rapid suppression was observed (p=0.001), whereas in the other groups, these results were much slower and not as obvious. Interestingly, again in the case of group C, the change in TNF-α concentration in wound tissue was most intensive (≈75% reduction), whereas the changes in other groups were not as obvious (≈50% reduction). After irradiation (658 nm), the VEGF expression increased significantly within the first two weeks, and then it decreased and maintained a stable level. In contrast, the TGFβ1 activity remained level, but always higher in comparison to other groups Conclusions: The effective healing of pressure ulcers is connected with laser irradiation at a wavelength of 658 nm. We believe that this effect is related to the inhibition of inflammatory processes in the wound and stimulation of angiogenesis and fibroblast proliferation at this specific radiation (based both on concentration of interleukins and TNF-α serum level and VEGF, TGFβ1, TNF-α activities in wound biopsies). Laser therapy at wavelengths of 940 and 808 nm does not significantly affect the above-mentioned repair processes, which explains its low effectiveness in the treatment of pressure ulcers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The ischaemia-reperfusion (I/R)-induced skin lesion has been identified as primary cause of pressure ulcers. To date, attempts to prevent pressure ulcers have not produced a significant improvement. Quercetin, one of the most widely distributed flavonoids in fruits and vegetables, exhibits its antioxidant and anti-inflammatory properties against many diseases, including ischaemic heart disease, atherosclerosis and renal injury. In vitro wound scratch assay was first used to assess the function of quercetin in wounding cell model. Next, animal pressure ulcers model was established with two cycles of I/R. The impact of quercetin in the wound recovery, immune cell infiltration and pro-inflammatory cytokines production was investigated in this model. Mechanistic regulation of quercetin at the wound site was also studied. Quercetin accelerated wound closure in cell scratch assay. Dose-response study suggested 1 μmol/L quercetin for in vivo study. In I/R injury model, quercetin treatment significantly accelerated wound closure, reduced immune cell infiltration and pro-inflammatory cytokines production. Signalling study showed quercetin treatment inhibited MAPK but not NFĸB activation. Quercetin treatment improved the wound healing process in I/R lesions by suppressing MAPK pathway. Our results supported that quercetin could be a potential therapeutic agent for pressure ulcers., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The roles of matrix metalloproteinase (MMP)9 in the control of pressure ulcers (PU) after hip fracture as well as how the rs1056629 in MMP9 3'UTR compromises the interaction between MMP9 and miR‑491 were explored. Online miRNA database (http://www.bioguo.org) was utilized to explore gene polymorphism in MMP9 3'UTR that might break the interaction between MMP9 and miRNA. Luciferase assay was utilized to confirm the miRNA targeted MMP9. Real‑time PCR, western blot analysis and immunohistochemistry were carried out to understand the roles of MMP9 in PU as well as how rs1056629 in MMP9 3'UTR compromises the interaction between MMP9 and miR‑491. rs1056629 in MMP9 3'UTR that compromised the interaction between MMP9 and four miRNAs including miR‑194‑3p, miR‑491, miR‑1915‑3p and miR‑941, and only miR‑491 among miR‑194‑3p, miR‑491, miR‑1915‑3p and miR‑941 decreased luciferase activity of wild‑type MMP9 3'UTR, and luciferase activities of mutant‑3 and mutant‑4 MMP9 3'UTR in miR‑491 overexpressing cells was comparable with scramble control. miR‑194‑3p, miR‑491, miR‑1915‑3p and miR‑941 levels in PU group was comparable with healthy control, and miR‑194‑3p, miR‑491, miR‑1915‑3p and miR‑941 in subjects carrying AA genotype was similar with those in AC and CC groups. MMP9 mRNA and protein, and histology score in subjects with PU were much higher, and were also much higher in AA group. Only miR‑491 mimic among miR‑194‑3p, miR‑491, miR‑1915‑3p and miR‑941 mimics downregulated the MMP9 level, and only miR‑491 inhibitor among miR‑194‑3p, miR‑491, miR‑1915‑3p and miR‑941 inhibitors upregulated the MMP9 level. Our study indicated that rs1056629 polymorphism could be a novel biomarker for predicting the occurrence of PU after a hip fracture.

Objective: To observe the phenomenon of apoptosis and expression of related proteins in injured muscle tissue during the formation of pressure injury, and to explore its mechanism of action on the pressure injury., Methods: Forty male Sprague-Dawley (SD) rats were divided into normal control group, 3, 5, 7 and 9 compression groups according to the random number table, with 8 rats in each group. The pressure injury models on the gracilis muscle of hind limbs were reproduced by using a way of cycle compression of ischemia/reperfusion (I/R) magnet. One cycle consisted of 12-hour compression, and followed by 12-hour release. The 5, 7, 9 compression groups were cut through after receiving 3 cycles. The normal control group did not receive any treatment. Muscle tissue specimens were harvested in the pressurized center at the end of the experiment (the same site for the normal control group), then the rats were sacrificed. The hematoxylin-eosin (HE) staining was used to examine the changes of muscle tissue morphology. The Hoechst 33258 staining was used to evaluate the apoptosis of muscle tissue. Western Blot was used to detect the expressions of heat shock protein 70 (HSP70), B-cell lymphoma-2 protein (Bcl-2) and Bcl-2 associated X protein (Bax)., Results: (1) HE staining showed that the compressed tissues appeared different degrees of pathological degradation, and the change of tissue morphology was more serious with the increase of the compression cycle. (2) Hoechst 33258 staining showed that the nuclei of compressed tissue showed condensed, compact morphology and granular fluorescence, and the number of apoptotic cells increased with the increase of the compression cycle. (3) Western Blot showed that with the increase of the compression cycle the protein expressions of HSP70 and Bax were gradually increased, and the protein expression of Bcl-2 was gradually decreased. Compared with the normal control group, the protein expression of HSP70 in the 9 compression group was increased with statistically significant differences (HSP70/GAPDH: 1.78±0.21 vs. 0.55±0.17, P < 0.01). The protein expression of Bax in the 7 and 9 compression groups were increased with statistically significant differences (Bax/GAPDH: 0.96±0.09, 0.98±0.02 vs. 0.67±0.07, both P < 0.01). The protein expression of Bcl-2 in the 3, 5, 7 and 9 compression groups were significantly decreased (Bcl-2/GAPDH: 0.17±0.03, 0.13±0.03, 0.14±0.03, 0.10±0.02 vs. 0.36±0.04, all P < 0.05)., Conclusions: Apoptosis can be induced by I/R in pressure injury tissues. Apoptosis induced by HSP70 and apoptosis factors Bcl-2 and Bax may be involved in the formation of pressure injury.

The hyaluronan (HA)-rich extracellular matrix plays dynamic roles during tissue remodeling. Versican and serum-derived HA-associated protein (SHAP), corresponding to the heavy chains of inter-α-trypsin inhibitor, are major HA-binding molecules in remodeling processes, such as wound healing. Versican G1-domain fragment (VG1F) is generated by proteolysis and is present in either remodeling tissues or the mature dermis. However, the macrocomplex formation of VG1F has not been clarified. Therefore, we examined the VG1F-containing macrocomplex in pressure ulcers characterized by chronic refractory wounds. VG1F colocalized with SHAP-HA in specific regions of the granulation tissue but not with fibrillin-1. A unique VG1F-SHAP-HA complex was isolated from granulation tissues using gel filtration chromatography and subsequent cesium chloride-gradient ultracentrifugation under dissociating conditions. Consistent with this molecular composition, recombinant versican G1, but not versican G3, interacted with the two heavy chains of inter-α-trypsin inhibitor. The addition of recombinant VG1 in fibroblast cultures enhanced VG1F-SHAP-HA complex deposition in the pericellular extracellular matrix. Comparison with other VG1F-containing macrocomplexes, including dermal VG1F aggregates, versican-bound microfibrils, and intact versican, highlighted the tissue-specific organization of HA-rich extracellular matrix formation containing versican and SHAP. The VG1F-SHAP-HA complex was specifically detected in the edematous granulation tissues of human pressure ulcers and in inflamed stages in a mouse model of moist would healing, suggesting that the complex provides an HA-rich matrix suitable for inflammatory reactions., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The ischemia-reperfusion (I/R) induced skin lesion has been identified as primary cause of pressure ulcer. Better understanding of the mechanism is required for new therapy development. Leucine rich repeat containing protein 19 (LRRC19) is a recently discovered transmembrane protein containing leucine-rich repeats and plays a role in immune response. To investigate the role of LRRC19 in pressure ulcers, mouse ulcer model was established with two cycles of I/R. The expression of LRRC19 was assessed during injury. siRNA mediated LRRC19 downregulation was applied to investigate the disease severity, immune cell infiltration and pro-inflammatory cytokines production. The primary skin fibroblasts were stimulated with IL-1β to dissect the molecular mechanism. LRRC19 was readily induced in I/R induced lesion site in a pattern mimicking the disease progress as measured by wound area. Knockdown of LRRC19 by siRNA significantly alleviated the disease severity and attenuated immune cell infiltration and pro-inflammatory cytokines production. In primary skin fibroblast model, siRNA knockdown of LRRC19 suppressed IL-1β mediated NFκB activation and its downstream cytokines production. LRRC19 was a novel factor for I/R-induced tissue damage by promoting NFκB dependent pro-inflammatory response. Our results supported that LRRC19 could be a potential therapeutic target for pressure ulcers.

Cutaneous ischemia-reperfusion (I/R) injury is associated with the early pathogenesis of cutaneous pressure ulcers (PUs). The objective of this study was to investigate the effect of mesenchymal stem cells (MSCs) injection on the formation of PUs after I/R injury and determine the underlying mechanisms. We found that the subcutaneous injection of MSCs into areas of I/R injured skin significantly suppressed the formation of PUs. I/R-induced vascular damage, hypoxia, oxidative DNA damage, and apoptosis were decreased by MSCs injection. Oxidative stress signals detected after I/R in OKD48 (Keap1-dependent oxidative stress detector, No-48-luciferase) mice were decreased by the injection of MSCs. In cultured fibroblasts, MSCs-conditioned medium significantly inhibited oxidant-induced reactive oxygen species (ROS) generation and apoptosis. Furthermore, endoplasmic reticulum (ER) stress signals detected after I/R in ERAI (ER stress-activated indicator) mice were also decreased by the injection of MSCs. These results suggest that the injection of MSCs might protect against the development of PUs after cutaneous I/R injury by reducing vascular damage, oxidative cellular damage, oxidative stress, ER stress, and apoptosis.

Pressure ulcers (PrUs)* are chronic wounds caused by a combination of factors, such as repetitive ischemia perfusion injury, bacterial colonization of the wound bed, local tissue hypoxia, or an altered cellular and systemic stress response. The objectives of this study were to analyze fragments of devitalized tissue of Stages III and IV PrUs and compare them with healthy tissue to evaluate the expression of the genes involved in wound inflammation. Samples of healthy skin from patients undergoing plastic surgery (n = 3) were collected, as well as from patients with devitalized tissue from Stages III and IV PrUs (n = 3) by means of sharp debridement. Gene expression analysis identified 5 up-regulated genes and 6 down-regulated genes in the devitalized tissue. Fibroblast cultures treated with devitalized tissue extract showed less attraction and cellular growth compared with the control group. Western blotting analysis showed a tendency of 3 particular genes to decrease in cell cultures treated with devitalized tissue extract. This study demonstrates that all of these mediators stimulate and promote inflammation in the wound bed and that a better understanding of the mechanisms of chronic wound development could lead to novel therapeutic strategies.

Purpose: The purpose of this study was to assess the level of matrix metalloproteinase-8 (MMP-8) and wound-healing outcome measures (length, width, and depth, exudate amount, and tissue type) in pressure injuries (PIs) of spinal cord-injured patients treated with negative pressure wound therapy (NPWT) using a novel negative pressure device versus PI treated with wet to moist gauze (conventional wound care)., Design: Randomized controlled trial., Subjects and Setting: Forty-four spinal cord-injured patients with stage 3 and 4 sacral PI participated in the study. The study setting was the Department of Orthopedic Surgery at King George's Medical University, in Lucknow, India., Methods: Twenty two subjects were randomly allocated to undergo NPWT via a novel negative pressure device, and 22 participants received conventional wound dressing (wet to moist gauze dressings). Pressure injuries were treated for 9 weeks or until wound closure. Levels of MMP-8 were analyzed in the tissues of PIs at weeks 0, 3, 6, and 9 by enzyme-linked immunosorbent assay., Results: Significantly lower levels of MMP-8 were observed in the NPWT group at week 6 and week 9. There were no significant changes in the length and width of PIs between the groups till week 3. Significant reduced length and width were observed in PIs of patients in the NPWT group at week 6 (P = .04) and week 9 (P = .001). Similarly, significant reduction in the depth of PIs was observed in the NPWT group at week 9 (P < .05). At the end of 9 week, levels of MMP-8 showed a positive correlation with reduction in the length, width, and depth of PIs in the NPWT group while in the conventional dressing group, negative correlation was observed in association with MMP-8 and the length, width, and depth of PIs. Exudate levels were significantly lower in the NPWT group compared with the conventional dressing group from week 3 (2.96 ± 0.21 vs 2.62 ± 0.49); this difference persisted through week 9 (1.35 ± 0.75 vs 0.14 ± 0.35). Conversion of slough into red granulation tissue was significantly higher in the NPWT group after week 6 (P = .001)., Conclusion: Reduced levels of MMP-8 and an increased rate of healing were found in patients allocated to treatment with a novel negative pressure device as compared to wet to moist gauze conventional dressing. The novel NPWT device used in this study reduced exudate production and enhanced the rate of formation of red granulation tissue.

Objective: To study the distribution and expressions of inflammatory, growth factors, apoptosis factors in the late stage of pressure ulcer chronic wounds., Methods: Twenty patients were recruited from the First Affiliated Hospital of Henan University during Oc-tomber 2013 to July 2015. Including twenty patients of stage Ⅲ,Ⅳ pressure ulcer, ten acute injury patients and six normal health persons. The histological changes of different wounds were observed by HE staining, the distribution of Caspase-3 protein in four groups was detected by immunohistochemistry technique. The expressions of mRNAs for interleukin (IL)-1β, interleukin (IL)-6, tumor necrosis factor-a (TNF-a), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2(KDR), fibroblast growth factors(bFGF) and fibrob-last growth factors receptor1 (FGFR1)were determined by real-time reverse transcription polymerase chain reaction., Results: Large numbers of inflammatory cells were found in the stage of Ⅲ, Ⅳpressure ulcer wound under HE staining. The levels of Caspase-3 were mainly localized in fibroblasts or endothelial cells. Compared with the other two groups, the expression of Caspase-3 in pressure ulcers groups was higher ( P < 0.01). The expressions of IL-1β, IL-6 and TNF-α were higher than those of the acute group and normal group. The expressions of VEGF, KDR, bFGF and FGFR1 were lower than those of the control group respectively., Conclusions: Overproduction or prolonged expression of in-flammatory factor and apoptosis factor, the expression of VEGF and its receptor KDR and bFGF and its receptor FGFR1 were significantly de-creased in the stage Ⅲ, Ⅳ pressure ulcer wound. These characteristics can be used to comprehensively evaluate etiology and treatment of pressure ulcer chronic wounds.

Human skin presents a large, easily accessible matrix that is potentially useful for diagnostic applications based on whole body metabolite changes-some of which will be volatile and detected using minimally invasive tools. Unfortunately, identifying skin biomarkers that can be reliably linked to a particular condition is challenging due to a large variability of genetics, dietary intake, and environmental exposures within human populations. This leads to a paucity of clinically validated volatile skin biomarker compounds. Animal models present a very convenient and attractive way to circumvent many of the variability issues. The rabbit (Leporidae) is a potentially logistically useful model to study the skin metabolome, but very limited knowledge of its skin metabolites exists. Here we present the first comprehensive assessment of the volatile fraction of rabbit skin metabolites using polydimethylsiloxane sorbent patch sampling in conjunction with gas chromatography/mass spectrometry. A collection of compounds that are secreted from rabbit skin was documented, and predominantly acyclic long-chain alkyls and alcohols were detected. We then utilized this animal model to study differences between intact skin and skin with early pressure ulcers, as the latter are a major problem in intensive care units. Four New Zealand female white rabbits underwent ulcer formation on one ear with the other ear as a control. Early-stage ulcers were created with neodymium magnets. Histologic analysis showed acute heterophilic dermatitis, edema, and micro-hemorrhage on the ulcerated ears with normal findings on the control ears. The metabolomic analysis revealed subtle but noticeable differences, with several compounds associated with the oxidative stress-related degradation of lipids found to be present in greater abundances in ulcerated ears. The metabolomic findings correlate with histologic evidence of early-stage ulcers. We postulate that the Leporidae model recapitulated the vascular changes associated with ulcer formation. This study illustrates the potential usefulness of the Leporidae model for skin metabolome studies. Additionally, skin metabolome analysis may enhance an understanding of non-skin sources such as urine or breath.

Pressure sores are a major complication in the bed-ridden older patient. In this report, we present the case of platelet rich plasma (PRP) application for the treatment of a pressure sore in an 88-year-old female affected by transfusion-dependent chronic inflammatory disease anemia associated with the congenital and inherited condition of thalassemic trait carrier. A weekly application schedule was planned athome, given the patient's debilitation and her decreased performance status as well as personal and family difficulties to go as outpatients at our treatment center. After 9 PRP applications, a remarkable sore improvement was achieved so that PRP was discontinued; nevertheless, sore rapidly improved until the full resolution and the complete closing after 4 months from the start of PRP treatment. Noteworthy, transfusion support was interrupted and a significant recovery and a sustained stabilization of hemoglobin (Hb) level at 1 year after ulcer healing were observed. The present case suggests that PRP application, performed athome in our case, is a feasible and effective treatment for pressure sores and related complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: Angelica dahurica is a well-known traditional Chinese Medicine (TCM), while little information is available about its effects on pressure sores. We aimed to investigate the clinical effect of Angelica dahurica on patients with I-II phase pressure sores, as well as the underlying mechanism., Methods: Patients (n = 98) with phase I and phase II pressure sores were enrolled and randomly assigned to control and treated groups. In addition to holistic nursing, patients in the control group received compound clotrimazole cream, while patients in the treated group received continuous 4 weeks of external application of Angelica dahurica dressing. Therapeutic effect was recorded, along with the levels of interleukin-8 (IL-8), epidermal growth factor (EGF), transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF). Besides, HaCaT cells were cultured with different concentrations of Angelica dahurica, and then cell viability, clone formation numbers, cell cycle, and levels of cyclin D1 and cyclin-dependent kinase (CDK) 2 were determined., Results: The total effective rate in the treated group was significantly higher than in the control group. Levels of IL-8, EGF, TGF-β, and VEGF were statistically increased by Angelica dahurica. In addition, the cell viability and clone formation numbers were significantly upregulated by Angelica dahurica in a dose-dependent manner. Also, the percentage of cells in G0/G1 phase, and levels of cyclin D1 and CDK2 were significantly elevated., Conclusion: Our results suggest that Angelica dahurica may provide an effective clinical treatment for I-II phase pressure sores.

Objective: To identify changes in concentrations of inflammatory mediators in plasma and urine after traumatic spinal cord injury (SCI) and before the occurrence of a first pressure ulcer., Design: Retrospective; secondary analysis of existing data., Setting: Acute hospitalization and inpatient rehabilitation sites at a university medical center., Participants: Individuals with a pressure ulcer and plasma samples (n=17) and individuals with a pressure ulcer and urine samples (n=15) were matched by age and plasma/urine sample days to individuals with SCI and no pressure ulcer (N=35)., Interventions: Not applicable., Main Outcome Measures: Plasma and urine samples were assayed in patients with SCI, capturing samples within 4 days after the SCI to a week before the formation of the first pressure ulcer. The Wilcoxon signed-rank test was performed to identify changes in the inflammatory mediators between the 2 time points., Results: An increase in concentration of the chemokine interferon-γ-induced protein of 10kd/CXCL10 in plasma (P<.01) and a decrease in concentration of the cytokine interferon-α in urine (P=.01) were observed before occurrence of a first pressure ulcer (∼4d) compared with matched controls., Conclusions: Altered levels of inflammatory mediators in plasma and urine may be associated with pressure ulcer development after traumatic SCI. These inflammatory mediators should be explored as possible biomarkers for identifying individuals at risk for pressure ulcer formation., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Pressure ulcer (PU) remains a common worldwide problem in all health care settings, it is synonymous with suffering. PU is a complex disease that is dependent on a number of interrelated factors. It involves multiple mechanisms such as physiological risk factors, chronic inflammation, oxidant-antioxidant imbalance and proteolytic attack on extracellular matrix by matrix metalloproteinases (MMP). Therefore, we propose that these wounds lead to molecular variations that can be detected by assessing biomarkers. In this study, we aimed to evaluate the major clinical elements and biological scars in Tunisian patients suffering from PU. Consistently, non-healing wound remains a challenging clinical problem. The complex challenges of the wound environment, involving nutrient deficiencies, bacterial infection, as well as the critical role played by inflammatory cells, should be considered because of their negative impact on wound healing. In addition, an imbalance between pro-oxidants and antioxidant systems seems to be more aggravated in patients with PU compared to healthy subjects. Of interest, this study provides further evidence to support a core role of the biological activity of MMP-9 in the pathogenesis of PU and indicates that the MMP9-1562 C/T (rs 3918242) functional polymorphism is associated with protection against this disease.