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OBJECTIVE To investigate the therapeutic effects of topical equine amniotic membrane (eAM) suspension following corneal wounding in a controlled experimental setting. PROCEDURES Equine amniotic membrane was collected, gamma irradiated, homogenized for topical suspension preparation, and cryopreserved. Corneoscleral rims harvested from fresh rabbit globes were wounded via keratectomy and were maintained in an air-liquid interface ex vivo corneal culture model. Treatment groups included topical gamma irradiated eAM suspension (n = 20) and a control group (n = 20). Re-epithelialization of the wound was assessed with daily photographic evaluation of area of fluorescein uptake (mm2 ). Corneal wound haze after a 21-day period was assessed by photographic analysis of haze area (mm2 ) and pixel intensity (0-255). Histologic processing of corneal tissue was performed, and protein identification of eAM suspension using Liquid chromatography-mass spectrometry (LC-MS). RESULTS The average day of complete corneal re-epithelialization in controls (5.5 ± 1.1) and topically treated (5.5 ± 0.6) corneas, and rates of reduction in area of fluorescein uptake over time did not significantly differ (p = .44). The corneal wound haze was significantly reduced in mean area by approximately 52% and intensity by 57% in corneas treated with topical eAM suspension (p

Insomnia is an adverse cancer outcome impacting mood, pain, quality of life, and mortality in cancer patients. Cognitive Behavioral Therapy (CBT) is an evidence-based treatment for diverse psychophysiological disorders, including pain and insomnia. Primarily studied in breast cancer, there is limited research on CBT within gynecology oncology. This study examined CBT effects on subjective and behavioral sleep outcomes: Sleep Efficiency (SE), Sleep Quality (SQ), Total Wake Time (TWT), Sleep Onset Latency (SOL), and Wake After Sleep Onset (WASO). Thirty-five women with insomnia status/post-surgery for gynecologic cancer were randomized to CBT for insomnia and pain (CBTi.p., N=18) or Psychoeducation (N=17). Sleep was assessed via sleep diaries and wrist-worn actigraphy at baseline (T1), post-intervention (T2), and two-month follow-up (T3). Intent-to-treat analyses utilizing mixed linear modeling examined longitudinal group differences on sleep controlling for age and advanced cancer. All participants demonstrated improved (1) subjective SE (0.5, p

This compendium is a follow-up to the 2018 American Diabetes Association compendium Diagnosis and Management of Diabetic Foot Complications. Whereas the first compendium offered a broad general overview of diabetic foot conditions, this second volume presents a detailed discussion of the prevention and treatment of diabetic foot infections (DFIs), a major contributor to high amputation rates among people with diabetes. The treatise begins from the viewpoint of basic science, describing the impact of infection on the healing process of experimental wounds. There follow overviews of biofilm development in chronic diabetic foot ulcers (DFUs), the microbiology of DFIs, and the crucial role of debridement in ensuring positive outcomes of DFI treatment. Next, the authors provide a practical guide to the diagnosis and clinical management of DFIs. Current controversies regarding the treatment of osteomyelitis are addressed, including the relative value of antibiotics versus surgery and the use of intravenous versus oral antibiotics. The compendium closes with a look at new topical treatments and the role of emerging technologies in infection control.This publication has been supported by unrestricted educational grants to the American Diabetes Association from Healogics, Inc., and Organogenesis, Inc.The opinions expressed are those of the authors and do not necessarily reflect those of Healogics, Inc., Organogenesis, Inc., or the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.

The Wound Healing Foundation (WHF) recognised a need for an unbiased consensus on the best treatment of chronic wounds. A panel of 13 experts were invited to a virtual meeting which took place on 27 March 2021. The proceedings were organised in the sub-sections diagnosis, debridement, infection control, dressings, grafting, pain management, oxygen treatment, outcomes and future needs. Eighty percent or better concurrence among the panellists was considered a consensus. A large number of critical questions were discussed and agreed upon. Important takeaways included that wound care needs to be simplified to a point that it can be delivered by the patient or the patient's family. Another one was that telemonitoring, which has proved very useful during the COVID-19 pandemic, can help reduce the frequency of interventions by a visiting nurse or a wound care center. Defining patient expectations is critical to designing a successful treatment. Patient outcomes might include wound specific outcomes such as time to heal, wound size reduction, as well as improvement in quality of life. For those patients with expectations of healing, an aggressive approach to achieve that goal is recommended. When healing is not an expectation, such as in patients receiving palliative wound care, outcomes might include pain reduction, exudate management, odour management and/or other quality of life benefits to wound care.

Objective Elevated body mass index (BMI), tobacco use, and sleep disturbance are common health concerns among women with gynecologic cancers. The extent to which these factors are associated with systemic inflammation in gynecologic cancers is unknown. This is a significant literature gap given that (a) chronic, systemic inflammation may mediate relationships between behavioral health factors and cancer outcomes; and (b) elevated BMI, tobacco use, and sleep disturbances can be modified via behavioral interventions. This study examined Interleukin-6 (IL-6) relations with BMI, tobacco use history, and sleep disturbances in patients undergoing surgery for suspected gynecologic cancer. Method Participants were 100 women (M age = 58.42 years, SD = 10.62 years) undergoing surgery for suspected gynecologic cancer. Smoking history was determined by participant self-report. Sleep quality/disturbance was assessed via the Pittsburgh Sleep Quality Index. BMI was abstracted from electronic health records. Presurgical serum IL-6 concentrations were determined using Enzyme-Linked Immunosorbent Assay. Results Controlling for the cancer type and stage, regression analyses revealed higher BMI, β = 0.258, p = .007, and former/current smoking status, β = 0.181, p = .046, were associated with higher IL-6. IL-6 did not differ between former and current smokers, β = 0.008, p = .927. Global sleep quality, sleep latency, and sleep efficiency were not associated with IL-6. Conclusions Higher BMI and any history of tobacco use predicted higher IL-6 among women undergoing surgery for suspected gynecologic cancers. Cognitive-behavioral interventions targeting primary and secondary obesity and tobacco use prevention may reduce systemic inflammation and optimize cancer outcomes in this population. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Biofilms are prevalent in non‐healing chronic wounds and implicated in delayed healing. Tolerance to antimicrobial treatments and the host's immune system leave clinicians with limited interventions against biofilm populations. It is therefore essential that effective treatments be rigorously tested and demonstrate an impact on biofilm across multiple experimental models to guide clinical investigations and protocols. Cadexomer iodine has previously been shown to be effective against biofilm in various in vitro models, against methicillin‐resistant Staphylococcus aureus biofilm in mouse wounds, and clinically in diabetic foot ulcers complicated by biofilm. Similarities between porcine and human skin make the pig a favoured model for cutaneous wound studies. Two antiseptic dressings and a gauze control were assessed against mature biofilm grown on ex vivo pig skin and in a pig wound model. Significant reductions in biofilm were observed following treatment with cadexomer iodine across both biofilm models. In contrast, silver carboxymethylcellulose dressings had minimal impact on biofilm in the models, with similar results to the control in the ex vivo model. Microscopy and histopathology indicate that the depth of organisms in wound tissue may impact treatment effectiveness. Further work on the promising biofilm efficacy of cadexomer iodine is needed to determine optimal treatment durations against biofilm.

Despite the understanding that wounds are a common problem affecting the individual, the health service and society as a whole, there continues to be a lack of a systematic, structured, evidence-based approach to wound management. The TIME principle was first published in 2003, 1 and has since been integrated by many into clinical practice and research. However, this tool has been criticised for its tendency to focus mainly on the wound rather than on the wider issues that the patient is presenting with. At an expert meeting held in London in 2018, this conundrum was addressed and the TIME clinical decision support tool (CDST) was elaborated upon. This article introduces the TIME CDST, explains why it is required and describes how its use is likely to benefit patients, clinicians and health-service organisations. It also explores the framework in detail, and shows why this simple and accessible framework is robust enough to facilitate consistency in the delivery of wound care and better patient outcomes. Finally, it outlines the next steps for the rollout, use and evaluation of the impact of the TIME CDST.

The 3rd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 12-14 October 2018 at the Women's College Hospital in Toronto, Ontario, Canada. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF) founded in the USA and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This cross-disciplinary meeting with experts from around the world was an opportunity to discuss the most recent advances in the study of hidradenitis suppurativa pathogenesis, epidemiology, classification, scoring systems, radiologic diagnosis, treatment approaches and psychologic assessment. Two special sessions this year were HS as a systemic disease and HS management guidelines. There were focused workshops on wound healing and ultrasound. There were two sessions primarily for patients and their families in the HS School programme: One workshop focused on mindfulness, and the second involved discussion among clinicians and patients about various disease aspects and the latest management. To facilitate networking between clinical and research experts and those early in their career, a mentoring breakfast was held.

Aim The aim of this study is to assess the effectiveness of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDI) with a broad spectrum epigenetic activity, in improving filtration bleb survival as an adjunct therapy to glaucoma filtration surgery (GFS) in the rabbit model. Materials and methods Eighteen New Zealand White rabbits underwent GFS in the left eye and were randomized to receive either a subconjunctival (SC) injection of 0.1 mL SAHA (9.25 μg/mL) or balanced saline solution (BSS) at the end of surgery, or a 3-minute intraoperative topical application of 0.4 mg/mL mitomycin-C (MMC). Bleb survival and histology were compared. Results Blebs of rabbits receiving injections of SAHA survived an average (mean ± SD) of 23.2 ± 2.7 days. SAHA rabbits showed a nonsignificant improvement over rabbits that received an injection of BSS, which had a mean survival time of 19.7 ± 2.7 days (p = 0.38) according to a one-way analysis of variance (ANOVA). Eyes receiving intraoperative topical MMC survived an average of 32.5 ± 3.3 days, which is significantly longer than both the control group treated with BSS (p = 0.01) and the experimental group treated with the SAHA (p = 0.0495). SAHA was well tolerated and showed no significant avascularity, necrosis, or conjunctival thinning. Conclusion Although it was well tolerated, a single intraoperative injection of SAHA did not significantly prolong bleb survival in the rabbit model. Clinical significance Epigenetic adjuncts hold promise for improving GFS outcome; however, future studies must continue to examine different administration protocols and dosages to substantiate their efficacy. How to cite this article Rodgers CD, Lukowski ZL, et al. Modulating Ocular Scarring in Glaucoma Filtration Surgery Using the Epigenetic Adjunct Suberoylanilide Hydroxamic Acid. J Curr Glaucoma Pract 2019;13(1):37–41.

The purpose of wound dressing or cover is to provide moist environment, reduce bioburden, promote granulation and epithelisation, shorten duration of inflammatory response, be useful as primary wound dressing and to prevent nosocomial infection...

Atopic Dermatitis (AD) is characterized by skin barrier disruption and an aberrant immune response. Doxycycline are tetracycline antibiotics broadly used systemically to treat inflammatory-dermatologic conditions. Several studies have shown doxycycline have anti-inflammatory and pro-healing properties, mainly by blocking tissue proteolytic activity. It is our hypothesis that daily application of a novel Doxycycline topical formulation in AD subjects will reduce severity of the disease, by blocking cutaneous proteases activity and restoring skin barrier function and inflammation. To test this hypotehsis we performed a proof of concept, open-label clinical study. Subjects enrolled in the study (n=15) applied NanoDOX® Hydrogel 1% daily for four weeks on a chosen eczematous area. Investigational drug was well tolerated, no local or systemic adverse events due to investigational drug were reported. Notably, a significant clinical improvement was observed based on a modified Eczema Area & Severity Index (EASI) score of the treated area from start of treatment to 14 and 28 days post treatment (p

Biofilms play a central role in the chronicity of non-healing lesions such as venous leg ulcers and diabetic foot ulcers. Therefore, biofilm management and treatment is now considered an essential part of wound care. Many antimicrobial treatments, whether topical or systemic, have been shown to have limited efficacy in the treatment of biofilm phenotypes. The antimicrobial properties of iodine compounds rely on multiple and diverse interactions to exert their effects on microorganisms. An expert panel, held in Las Vegas during the autumn Symposium on Advanced Wound Care meeting in 2018, discussed these properties, with the focus on iodine and iodophors and their effects on biofilm prevention and treatment.

Dermatologists are exposed to wound healing during their training. Unfortunately, only minimal time is dedicated to this important subfield of medicine. Nevertheless, solid background in dermatology provides training physicians a much easier route to expand their knowledge of wound healing. Chronic wounds are opened and have the propensity to be infected; this may stall the healing process in milder cases, but may actually have more devastating outcome if the infection is not well controlled. There are some conditions when chronic wounds may appear infected, but they are not, and it is essential to differentiate imminent infection from conditions that may merely mimic infection. Finally, we would like to shed some light and provide enablers for dermatologist in wound healing with emphasis on infection control.

In vitro screening and testing of drugs and devices is necessary, but in vitro conditions differ greatly from those found in vivo. These differences can lead to false promises of efficacy, or can hide problems of tissue compatibility. Models with ex vivo tissues can be highly valuable bridges which provide relevant matrices for testing [1], [2], [3], [4], [5], [6], [7], [8], [9]. Ex vivo tissue models which are closer both biochemically and biophysically can provide useful feedback in a more time- and cost-efficient manner. Herein we describe an ex vivo corneal model for use in drug delivery testing and corneal infection modeling [10]. The protocol covers the tissue harvesting, sterilization, inoculation, and bacterial load quantification. We envision that the model can be used to study bacterial physiology on metabolizable matrices and to study the direct effects of microbial colonization on the cornea's integrity and clarity.•Devitalized cornea.•Non-submersed conditions.•Contact lens compatible., Graphical abstract Image, graphical abstract

In this study, capillary alginate gel (Capgel™), a collagen and alginate based self-assembling biomaterial, was used as a cellular scaffold for the treatment of ischemic, full-thickness dermal woun...

Background This study evaluated whether a multi-ingredient surfactant colloidal silver technology was noninferior to a 4% chlorhexidine gluconate (CHG) antiseptic on immediate and persistent antimicrobial activity. Methods The inguinal regions of 81 healthy adults were demarcated into 4 quadrants, and 3 were used for testing each product at baseline, 10 minutes, and 6 hours postapplication. The log of the number of colony forming units was obtained using a cylinder sampling technique. The 95% confidence interval of the test product to the control product with a margin of 0.65 was established as the upper limit of noninferiority. Results A total of 81 individuals were enrolled. The colloidal silver product was found to be noninferior to 4% CHG at both 10 minutes and 6 hours postapplication. Conclusions The colloidal silver-based product was noninferior to the 4% CHG product at 10 minutes and 6 hours postapplication.

The characteristic clinical signs of chronic wounds, which remain in a state of prolonged inflammation, include increased production of devitalised tissue and exudate, pain and malodour. The presence of necrotic tissue, slough and copious exudate encourages microbial proliferation, potentially resulting in planktonic and/or biofilm infection. For patients, the consequences can include leakage of exudate, pain and reduced mobility, which can impair their ability to socialise and perform activities of daily living. This can severely reduce their quality of life and wellbeing. Concentrated surfactant-based gels (Plurogel and Plurogel SSD) are used in wound cleansing to help manage devitalised tissue. In vitro studies indicate they can sequester planktonic microbes and biofilm from the wound bed, although there is, limited clinical evidence to support this. A group of health professionals who have used this concentrated surfactant gel, in combination with standard care, in their clinical practice for several years recently met at a closed panel session. Here, they present case studies where topical application of these gels resulted in positive clinical outcomes in previously long-standing recalcitrant wounds. In all cases, the reduction in inflammation and bioburden alleviated symptoms that previously severely impaired health-related quality of life and wellbeing.

Infected tissues in the feet of people with diabetes in the form of a diabetic foot ulcer (DFU) present a complex pathology for clinicians to manage. This is partly attributed to the multi-factorial nature of the disease, which may include; altered foot architecture leading to excessive plantar pressures and frictional forces peripheral arterial disease and loss of protective sensation. In addition, to the above co-morbid variables, it is understood that a delayed wound healing state may be perpetuated by the presence of microorganisms residing in the wound tissue. The microbiology of chronic DFUs has often been reported as being polymicrobial. Of growing interest is the presence and potential role of anaerobic microorganisms in the pathology of DFUs and how they may contribute to the infective process or delayed healing. The presence of anaerobes in DFUs has been greatly underestimated, largely due to the limitations of conventional culture methods in identifying them from samples. Advancements in molecular and microscopy techniques have extended our view of the wound microbiome in addition to observing the growth and behaviour (planktonic or biofilm) of microorganisms in situ. This review paper will reflect on the evidence for the role and significance of anaerobes in DFUs and infection. A focus of this review will be to explore recent advancements in molecular genomics and microscopy techniques in order to better assess the roles of anaerobic bacteria in chronic DFUs and in biofilm-based wound care.

Early awareness and management of bacterial burden and biofilm is essential to wound healing. Semi-quantitative analysis of swab or biopsy samples is a relatively simple method for measuring wound microbial load. The accuracy of semi-quantitative culture analysis was compared to ‘gold standard’ quantitative culture analysis using 428 tissue biopsies from 350 chronic wounds. Semi-quantitative results, obtained by serial dilution of biopsy homogenates streaked onto culture plates divided into 4 quadrants representing occasional, light, moderate, and heavy growth, were compared to total bacterial load quantified as colony-forming units per gram (CFU/g). Light growth, typically considered an insignificant finding, averaged a clinically significant 2.5 × 105 CFU/g (SE = 6.3 × 104 CFU/g). Occasional growth (range: 102–106 CFU/g) and light growth (103–107 CFU/g) corresponded to quantitative values that spanned a 5-log range, moderate and heavy growth corresponded to a range of 4-log and 6-log, respectively, with a high degree of overlap in range of CFU/g per category. Since tissue biopsy and quantitative culture cannot be widely practiced and semi-quantitative analysis is unreliable, other clinically relevant approaches are required to determine wound bioburden and guide best management practices. Fluorescence imaging is a point-of-care technology that offers great potential in this field.

Previous work has demonstrated that a surfactant-based dressing was capable of eliminating any evidence of pre-existing biofilms from an ex vivo porcine skin wound model. Herein, the authors test both the surfactant's ability to prevent biofilm formation and its ability to eliminate Acinetobacter baumannii biofilms. To test biofilm formation inhibition, porcine skin explants were inoculated and incubated for 4 hours before treatment. The explants were then dressed with test or control materials. To test biofilm elimination, mature 3-day biofilms were established and then treated and wiped daily. Explants from each group were harvested daily, and total and biofilm-associated bacterial counts were generated up through day 3 posttreatment. The control explants developed a biofilm with ~106 CFU over the course of 3 days for each of the bacteria tested. The surfactant-treated samples had viable bacteria, but with the exception of a single time point for Staphylococcus aureus without silver sulfadiazine, there was no biofilm formation. Unlike previous results, the surfactants could not eliminate the A. baumannii biofilm, unless it was formulated with relevant antibiotics. The surfactant was effective in preventing the formation of biofilms over a 3-day period. Unlike the authors' previous results, the daily surfactant-based approach alone did not eliminate the A. baumannii biofilms unless relevant antibiotics were included. The data suggest that the surfactants can prevent biofilm formation, but that in the case of a confirmed A. baumannii biofilm, the surfactant must include antibiotics.

Objectives Test the performance of topical antimicrobial wound solutions against microbial biofilms using in vitro, ex vivo and in vivo model systems at clinically relevant exposure times. Methods Topical antimicrobial wound solutions were tested under three different conditions: (in vitro) 4% w/v Melaleuca oil, polyhexamethylene biguanide, chlorhexidine, povidone iodine and hypochlorous acid were tested at short duration exposure times for 15 min against 3 day mature biofilms of Staphylococcus aureus and Pseudomonas aeruginosa; (ex vivo) hypochlorous acid was tested in a porcine skin explant model with 12 cycles of 10 min exposure, over 24 h, against 3 day mature P. aeruginosa biofilms; and (in vivo) 4% w/v Melaleuca oil was applied for 15 min exposure, daily, for 7 days, in 10 patients with chronic non-healing diabetic foot ulcers complicated by biofilm. Results In vitro assessment demonstrated variable efficacy in reducing biofilms ranging from 0.5 log10 reductions to full eradication. Repeated instillation of hypochlorous acid in a porcine model achieved

Surfactants are widely used as detergents, emulsifiers, wetting agents, foaming agents and dispersants in the cosmetics, hygiene, food and oil industries. Their use in a clinical setting is also common, particularly within the field of wound care. Many wound cleansers contain surfactants and subsequently there is available data that shows the growing potential of these wound cleansers in the enhancement of wound closure. The presence of microorganisms in wounds has been recognised as a significant factor that delay healing. In complex or chronic wounds that are complicated by biofilms, persistent inflammation or the production of non-viable tissue and slough, the use of surfactants has been shown to aid in the removal of these barriers to wound healing. The use of concentrated surfactant(poloxamer) based wound dressings represent an important component of wound management. Consequently, this article will discuss the effect of clinically used surfactants, with specific focus on a concentrated poloxamer for use against wound biofilm.

OBJECTIVE: Healthcare systems are being challenged to manage increasing numbers of nonhealing wounds. Wound dressings are one of the first lines of defense in wound management, and numerous options exist. The oxidized regenerated cellulose (ORC)/collagen dressing may offer healthcare providers a robust and cost-effective tool for use in a variety of wounds. DESIGN: A multidisciplinary panel meeting was convened to discuss the use of ORC/collagen dressings in wound care and provide practice recommendations. A literature search was conducted to provide a brief review of the peer-reviewed studies published between January 2000 and March 2016 to inform the meeting. SETTING: A 2-day panel meeting convened in February 2017. PARTICIPANTS: Healthcare providers with experience using ORC/collagen dressings. This multidisciplinary panel of 15 experts in wound healing included podiatrists, wound care specialists (doctors, certified wound care nurses, and research scientists), and an orthopedist. RESULTS: The literature search identified 58 articles, a majority of which were low levels of evidence (69.3% were level 3 or lower). Panel members identified wound types, such as abrasions, burns, stalled wounds, diabetic foot ulcers, and pressure injuries, where ORC/collagen dressing use could be beneficial. Panel members then provided recommendations and technical pearls for the use of ORC/collagen dressings in practice. Barriers to ORC/collagen dressing use were discussed, and potential resolutions were offered. CONCLUSIONS: An ORC/collagen dressing can be a critical tool for clinicians to help manage a variety of wounds. Clinical and economic studies comparing standard-of-care dressings and plain collagen dressings to ORC/collagen dressings are needed.

Background: Despite a growing consensus that biofilms contribute to a delay in the healing of chronic wounds, conflicting evidence pertaining to their identification and management can lead to uncertainty regarding treatment. This, in part, has been driven by reliance on in vitro data or animal models, which may not directly correlate to clinical evidence on the importance of biofilms. Limited data presented in human studies have further contributed to the uncertainty. Guidelines for care of chronic wounds with a focus on biofilms are needed to help aid the identification and management of biofilms, providing a clinical focus to support clinicians in improving patient care through evidence-based medicine. Methods: A Global Wound Biofilm Expert Panel, comprising 10 clinicians and researchers with expertise in laboratory and clinical aspects of biofilms, was identified and convened. A modified Delphi process, based on published scientific data and expert opinion, was used to develop consensus statements that could help identify and treat biofilms as part of the management of chronic nonhealing wounds. Using an electronic survey, panel members rated their agreement with statements about biofilm identification and treatment, and the management of chronic nonhealing wounds. Final consensus statements were agreed on in a face-to-face meeting. Results: Participants reached consensus on 61 statements in the following topic areas: understanding biofilms and the problems they cause clinicians; current diagnostic options; clinical indicators of biofilms; future options for diagnostic tests; treatment strategies; mechanical debridement; topical antiseptics; screening antibiofilm agents; and levels of evidence when choosing antibiofilm treatments. Conclusion: This consensus document attempts to clarify misunderstandings about the role of biofilms in clinical practice, and provides a basis for clinicians to recognize biofilms in chronic nonhealing wounds and manage patients optimally. A new paradigm for wound care, based on a stepped-down treatment approach, was derived from the consensus statements.

Bacterial biofilms are surface-attached communities of slow-growing or non-replicating bacteria tolerant to conventional antibiotic therapies. Although biofilms are known to occur in ca. 80% of all bacterial infections, no therapeutic agent has been developed to eradicate bacteria housed within biofilms. We have discovered that nitroxoline, an antibacterial agent used to treat urinary tract infections, displays broad-spectrum biofilm-eradicating activities against major human pathogens, including drug-resistant Staphylococcus aureus and Acinetobacter baumannii strains. In this study, the effectiveness of nitroxoline to eradicate biofilms was determined using an in vitro [minimum biofilm eradication concentration (MBEC) = 46.9 µM against A. baumannii] and ex vivo porcine skin model (2-3 log reduction in viable biofilm cells). Nitroxoline was also found to eradicate methicillin-resistant S. aureus (MRSA) persister cells in non-biofilm (stationary) cultures, whereas vancomycin and daptomycin were found to be inactive. These findings could lead to effective, nitroxoline-based therapies for biofilm-associated infections.

The presence of biofilms in chronic non-healing wounds, has been identified through in vitro model and in vivo animal data. However, human chronic wound studies are under-represented and generally report low sample sizes. For this reason we sought to ascertain the prevalence of biofilms in human chronic wounds by undertaking a systematic review and meta-analysis. Our initial search identified 554 studies from the literature databases (Cochrane Library, Embase, Medline). After removal of duplicates, and those not meeting the requirements of inclusion, nine studies involving 185 chronic wounds met the inclusion criteria. Prevalence of biofilms in chronic wounds was 78.2 % (confidence interval [CI 61.6–89, p

Bacteria have been found to form multicellular aggregates which have collectively been termed "biofilms." It is hypothesized that biofilm formation is a means to protect bacterial cells including protection form the immune response of humans. This protective mechanism is believed to explain persistent chronic wound infections. At times, the biofilms are abundant enough to see, and remove by simple wiping. However, recent evidence has shown that the removal of these visible portions are not sufficient, and that biofilms can continue to form even with daily wiping. In this work, we tested an approach to detect the biofilms which are present after clinically wiping or sharp wound debridement. Our method is based on a variation of impression cytology in which a nitrocellulose membrane was used to collect surface biofilm components, which were then differentially stained. In this prospective study, members of an interdisciplinary pressure ulcer team at a university hospital tested our method's ability to predict the generation of wound slough in the week that followed each blotting. A total of 70 blots collected from 23 pressure ulcers produced 27 wounds negative for staining and 43 positive. In the negative blots 55.6% were found to have decreased wound slough, while 81.4% with positive staining had either increase or unchanged wound slough generation. These results lead to an odds ratio of positive blotting cases of 9.37 (95% confidence intervals: 2.47-35.5, p = 0.001) for slough formation; suggesting that the changes in wound slough formation can be predicted clinically using a non-invasive wound blotting method.

OBJECTIVE To develop and assess a novel ex vivo corneal culture technique involving an agarose-based dome scaffold (ABDS) for use as a model of in vivo corneal wound healing in dogs and rabbits. SAMPLE Corneas from clinically normal dogs (paired corneas from 8 dogs and 8 single corneas) and rabbits (21 single corneas). PROCEDURES 8 single dog corneas (DCs), 1 DC from each pair, and 10 rabbit corneas (RCs) were wounded with an excimer laser; 1 DC from each pair and 11 RCs remained unwounded. Corneas were cultured for 21 days on ABDSs (8 pairs of DCs and all RCs) or on flat-topped scaffolds (8 single DCs). The surface area of corneal fluorescein retention was measured every 6 (DCs) or 12 (RCs) hours until full corneal epithelialization was detected. Changes in corneal clarity were evaluated at 0, 7, 14, and 21 days. RESULTS Median time to full epithelialization for wounded dog and rabbit corneas was 48 and 60 hours, respectively; among wounded DCs, time to full epithelization did not differ by scaffold type. After 21 days of culture on ABDSs, all DCs and RCs that epithelialized developed a circular, diffuse, cloud-like pattern of optical haze, whereas DCs cultured on flat-topped scaffolds developed a focal, crater-like region of optical haze. All corneas on the ABDSs maintained convex curvature throughout the study. CONCLUSIONS AND CLINICAL RELEVANCE Wounded ex vivo DCs and RCs cultured on ABDSs reliably epithelialized, formed optical haze (consistent with in vivo wound healing), and maintained convex curvature. This culture technique may be adaptable to other species.

Objectives Clinicians have increasingly adopted the widespread use of topical agents to manage chronic wound infections, despite limited data on their effectiveness in vivo. This study sought to evaluate the evidence for commonly employed topical agents used in wounds for the purpose of treating chronic infections caused by biofilm. Method We included in vitro, animal and human in vivo studies where topical agents were tested for their efficacy against biofilms, for use in wound care. For human studies, we only included those which utilised appropriate identification techniques for visualising and confirming the presence of biofilms. Result A total of 640 articles were identified, with 43 included after meeting eligibility. In vitro testing accounted for 90% (n = 39) of all included studies, five studies using animal models and three human in vivo studies. Sixteen different laboratory models were utilised, with the most frequent being the minimum biofilm eradication concentration (MBEC™) / well plate assay (38%, n = 15 of 39). A total of 44 commercially available topical agents were grouped into twelve categories with the most commonly tested agents being silver, iodine and polyhexamethylene biguanide (PHMB). In vitro results on efficacy demonstrated iodine as having the highest mean log10 reductions of all agents (4.81, ±3.14). Conclusion There is large disparity in the translation of laboratory studies to researchers undertaking human trials relating to the effectiveness of commercially available topical agents. There is insufficient human in vivo evidence to definitively recommend any commercially available topical agent over another for the treatment of chronic wound biofilms. The heterogeneity identified between study designs (in vitro to in vivo) further limits the generalisability of results.

The prevalence and incidence of chronic venous leg ulcers (CVLUs) are increasing worldwide, as are the associated financial costs. Although it has long been known that their underlying etiology is venous insufficiency, the molecular aspects of healing versus nonhealing, as well as the psychoneurologic symptoms (PNS; pain, cognitive dysfunction, fatigue, depression, and anxiety) associated with CVLUs remain understudied. In this biobehaviorally focused review, we aim to elucidate the complex mechanisms that link the biological and molecular aspects of CLVUs with their PNS. Innovations in “omics” research have increased our understanding of important wound microenvironmental factors (e.g., inflammation, microbial pathogenic biofilm, epigenetic processes) that may adversely alter the wound bed’s molecular milieu so that microbes evade immune detection. Although these molecular factors are not singularly responsible for wound healing, they are major components of wound development, nonhealing, and PNS that, until now, have not been amenable to systematic study, especially over time. Further, this review explores our current understanding of the molecular mechanisms by which the immune activation that contributes to the development and persistence of CVLUs also leads to the development, persistence, and severity of wound-related PNS. We also make recommendations for future research that will expand the field of biobehavioral wound science. Biobehavioral research that focuses on the interrelated mechanisms of PNS will lead to symptom-management interventions that improve quality of life for the population burdened by CVLUs.

Products that provide a protective skin barrier play a vital role in defending the skin against the corrosive effect of bodily fluids, including wound exudate, urine, liquid faeces, stoma output and sweat. There are many products to choose from, which can be broadly categorised by ingredients. This article describes the differences in mechanisms of action between barrier products comprising petrolatum and/or zinc oxide, silicone film-forming polymers and cyanoacrylates, and compares the evidence on them. The literature indicates that all types of barrier product are clinically effective, with little comparative evidence indicating that any one ingredient is more efficacious than another, although film-forming polymers and cyanoacrylates have been found to be easier to apply and more cost-effective. However, laboratory evidence, albeit limited, indicates that a concentrated cyanoacrylate produced a more substantial and adherent layer on a porcine explant when compared with a diluted cyanoacrylate and was more effective at protecting skin from abrasion and repeated exposure to moisture than a film-forming polymer. Finally, a silicone-based cream containing micronutrients was found to significantly reduce the incidence of pressure ulceration when used as part of a comprehensive prevention strategy.

Corneal infections are treated by multiple instillations of eye drops each day. This study aims to investigate the effectiveness of ofloxacin-loaded contact lenses as prolonged release devices for the treatment of bacterial keratitis. Two silicone hydrogel contact lenses (SHCLs) Senofilcon A (ACUVUE OASYS®) and Narafilcon A (ACUVUE TRUEYE®) were modified by incorporation of ofloxacin alone or with vitamin E (VE). The drug uptake and in vitro release kinetics were investigated and the antibacterial efficacy was assessed against Staphylococcus aureus and Pseudomonas aeruginosa in an ex vivo rabbit corneal model. The in vitro studies showed a higher uptake (p ≤ 0.05) and longer duration of release by Narafilcon A lenses compared to the Senofilcon A lenses. The addition of VE led to a significant increase in duration of release (p 0.05) for both lenses. The ex vivo studies confirmed the effectiveness of the ofloxacin-loaded lenses in the reduction of bacterial load to clinically insignificant levels and ofloxacin-vitamin E-loaded Narafilcon A lenses in the reduction of bacteria on the corneas to undetectable levels. Antibiotic-loaded lenses are effective in the treatment of ocular infections. Incorporation of vitamin E will sustain this effect and eliminate the need for multiple instillations of eye drops.

Purpose To evaluate the effect of topical suberanilohydroxamic acid (SAHA) and 5-methyl-1-phenyl-2[1H]-pyridone (pirfenidone) on the degree of corneal haze in the stromal wounded ex vivo canine cornea. Methods Twenty-four corneoscleral rims from normal dogs were uniformly wounded with an excimer laser and placed into culture medium with an air-liquid interface. The control group (n = 8) contained placebo-treated corneas. Treatment group 1 (n = 8) received SAHA topically every 6 hours. Treatment group 2 (n = 8) received pirfenidone topically every 6 hours. Each cornea was fluorescein stained and macrophotographed every 6 hours to assess epithelialization rate. All corneas were also macrophotographed weekly to assess optical clarity (haze). Images were analyzed for differences in pixel intensity between wounded (haze) and unwounded (nonhaze) regions, and haze surface area for each cornea was calculated. Results The mean epithelialization time was 47.25 hours in the control group, 45.00 hours in the SAHA group, and 43.50 hours in the pirfenidone group, revealing no significant difference (P = 0.368). The median difference in pixel intensity between haze and nonhaze areas was 21.5 in the control group, 8.0 in the SAHA group, and 8.0 in the pirfenidone group, which is significant (P < 0.01). The median haze surface area was 12.96 mm2 in the control group, 5.70 mm2 in the SAHA group, and 5.92 mm2 in the pirfenidone group, which is significant (P < 0.01). Conclusions Stromal-wounded ex vivo canine corneas exhibited greater optical clarity when treated with SAHA and pirfenidone than when placebo treated at 21 days. There was no significant difference in epithelialization rate between groups. Corneal contour was correlated with geographic haze distribution.

Proteinases are enzymes that can digest other proteins. In chronic wounds, a sub-class of these enzymes with the ability to degrade the extracellular matrix (matrix metalloproteinases, MMPs) have been found to both inhibit healing and to be able to aid in enzymatically debriding a wound. Enzymatic debridement using the enzymes present in a wound is generally called autolytic debridement. Clinicians seeking to employ autolytic debridement typically use occlusive materials such as medical honey, alginate dressings and other occlusive dressings. A relatively new class of gel dressings comprised of surfactants are now available for clinical use. A variety of surfactants are used in the study of MMP biochemistry. Surfactants can deactivate MMPs or can enhance their activity, depending on the surfactant. In order to begin to understand how the MMPs found in chronic wounds would respond to these new dressings, we tested a serial dilution series of two of the currently available surfactant-based dressings to determine their effects on four separate MMPs. The dose-response versus MMP activity of bacterial collagenase, host-derived MMP-8 and MMPs-2 and -9 was assessed using a simple mix-and-read fluorescent peptide activity assay. The enzyme's native activity in the absence of the gel was used to compare against the surfactant-treated samples. We found that the surfactant affected the proteinase activity differently for each enzyme. The activity of the bacterial collagenase was increased at low concentrations but slightly inhibited as the concentrations increased. The host MMP-8 collagenase responded similarly in that it was inhibited at higher concentrations. Interestingly, both MMP gelatinases presented with substantially increased activities, with MMP-2 increased to 200% of native activity, while MMP-9 presented with an increase of 300% activity over the same concentration range. MMPs appear to respond to a surfactant-based gel dressing differentially, with the MMP most commonly elevated in chronic wounds having the highest boost to activity. In wounds with elevated MMPs, our data suggest that the use of these surfactant-based dressings would be expected to enhance the activity of MMPs 2 and 9 gelatinases while simultaneously inhibiting MMP-8 collagenase. Hypothetically, this imbalanced effect would support a protection of the native dermal collagen and removal of denatured materials. However, the demonstration of these anticipated consequences is still being investigated.

Bacterial biofilms have been found in many, if not all, chronic wounds. Their excessive extracellular matrix secretion and the metabolic changes that they undergo render them highly tolerant of many antibiotic and antimicrobial treatments. Physical removal and/or disruption are a common approach to treating wounds suspected of having bacterial biofilms. While many of these techniques use mechanical energy as the primary means of removal, we have begun to investigate if surfactants could facilitate the removal of bacterial biofilms, or if they might sensitise the biofilms to antimicrobial interventions. We tested a new surfactant-based wound gel on an ex vivo porcine skin explant model infected with a functionally tolerant 3-day biofilm. The wounds were dressed with a surfactant-based gel directly on the wound or with moistened gauze. The wounds were then wiped daily with moistened gauze, and the gel or gauze was re-applied. Each day, an explant from each group was harvested and tested for total viable bacteria counts and viable biofilm-protected bacteria counts. The results show that daily wiping with moistened gauze led to an initial decrease of bacteria, but by day 3, the biofilm had been fully re-established to the same level prior to the beginning of treatment. For the surfactant-based treatment, there was no detectable functional biofilm after the first treatment. The gauze control, which was also subjected to daily wiping, still contained functional biofilms, indicating that this result was not due to wiping alone. The total bacteria in the surfactant-treated explants steadily decreased through day 3, when there were no detectable bacteria, while the wiping-only control bacteria counts remained steady. The use of a moist gauze to wipe the visually apparent slime off of a wound appears to be insufficient to reduce biofilm over a 3-day period. Daily application of the surfactant gel dressing and wiping reduced the biofilm to undetectable levels within 3 days in a skin explant model. A 3-day regimen of dressing the wound model with a surfactant gel followed by gentle removal of the gel by wiping with a moistened gauze appears to be a simple and adequate approach to removing a bacterial biofilm infection in an ex vivo model. Additional clinical evidence is needed to determine if this promising approach can perform the same in clinically infected chronic wounds.

Nearly 12 million wounds are treated in emergency departments throughout the United States every year. The limitations of current treatments for complex, full-thickness wounds are the driving force for the development of new wound treatment devices that result in faster healing of both dermal and epidermal tissue. Here, a bilayered, biodegradable hydrogel dressing that uses microarchitecture to guide two key steps in the proliferative phase of wound healing, re-epithelialization, and revascularization, was evaluated in vitro in a cell migration assay and in vivo in a bipedicle ischemic rat wound model. Results indicate that the Sharklet™-micropatterned apical layer of the dressing increased artificial wound coverage by up to 64%, P = 0.024 in vitro. In vivo evaluation demonstrated that the bilayered dressing construction enhanced overall healing outcomes significantly compared to untreated wounds and that these outcomes were not significantly different from a leading clinically available wound dressing. Collectively, these results demonstrate high potential for this new dressing to effectively accelerate wound healing.

To determine how collagen production by tympanic membrane fibroblasts is affected by ciprofloxacin at levels found in eardrops.Prospective, controlled, and blinded cell culture study.Academic tertiary medical center.Cell culture of mouse fibroblasts.A primary fibroblast culture was established from mouse tympanic membranes. Fibroblasts were cultured until they were 75% confluent, then treated with dilute hydrochloric acid (control) or ciprofloxacin (0.01% or 0.3%) for 24 or 72 hours for Western blotting and for 24 or 48 hours for cytotoxicity assay. Cells were observed with phase-contrast microscope. Western blotting was performed for collagen type 1 α1 (collagen 1A1) and α-tubulin.Fibroblasts treated with 0.01% and 0.3% ciprofloxacin for 24 hours had lower levels of collagen 1A1 (P = .0005 and P.0001, respectively) and α-tubulin (both P.0001) than control fibroblasts. Collagen 1A1 and α-tubulin levels were lower in fibroblasts treated with 0.3% than with 0.01% ciprofloxacin (P = .02 and P = .014). After 72 hours, 0.3% ciprofloxacin completely eliminated collagen 1A1 and α-tubulin (P.001). Cells treated with 0.01% ciprofloxacin for 72 hours also had lower collagen 1A1 (P.0001) and α-tubulin (P = .005) as compared with the control. Seventy-two-hour incubation in 0.01% or 0.3% ciprofloxacin resulted in lower levels of collagen 1A1 (P = .009 and P.0001, respectively) and α-tubulin (P = .007 and P.0001, respectively) than 24-hour incubation. Cytotoxicity assay and phase-contrast microscopy mirrored these findings.Treatment of tympanic membrane fibroblasts with 0.3% ciprofloxacin, as found in eardrops, reduces fibroblast viability and collagen and α-tubulin protein levels. These findings could explain tympanic membrane healing problems associated with quinolone eardrops.

Introduction Deciding when to graft a burn wound is instrumental in acute reconstruction. A technology capable of predicting autograft success would help optimize timing of initial debridement and grafting. In prior work, members of our team developed a point-of-care proteinase assay capable of predicting delayed wound healing in chronic wounds. In the work reported here, we seek to quantify these proteolytic enzymes in acute burn wounds in an effort to ultimately determine whether a quantitative assessment of proteinase activity in a burn wound might predict successful healing of autograft. Methods Eight burn patients were taken to the operating room for autografting. Tissue samples were obtained from unique sites, as well as swabs of wounds pre- and post-excision. A point-of-care proteinase assay determined initial rates of fluorescence, which correlates with the amount of proteolytic enzyme activity. Autograft sites were assessed after two weeks, with ≥50% take considered successful and < 50% take deemed unsuccessful. Initial rates of fluorescence were compared. These groups were analyzed using two-sided student’s t tests, with p< 0.05 identified as significant. Results The pre-excision group initial rate was significantly higher than the post-excision group (p=0.0006). The tissue group initial rate was also significantly higher than the post-excision group (p = 0.0028). We also compared pre-excision initial rates of enzymatic activity between successful autografts (n=10, 18.34±20.90 RFU/min) and unsuccessful autografts (n=5, 4.32±4.62 RFU/min) with p = 0.169. Conclusions Multiple findings indicate the potential of this assay to differentiate burn wounds based on proteinase activity. Pre-excision tissue beds contained significantly higher rates of proteinase activity compared to excised and debrided tissue beds (p = 0.0006). This is consistent with burn wound morphology, as proteolytic enzymes function to debride damaged tissue and promote angiogenesis in acute wounds. Interestingly, initial rates of proteolytic enzymatic activity in pre-excised wounds of successful autografts trended towards significance compared to unsuccessful autografts (p = 0.169), suggesting that these proteolytic enzymes reflect an overall healthy wound bed, the presence of which could portend a heightened chance for autograft success. Applicability of Research to Practice This pilot study confirms the presence of proteinase activity in acute burn wounds utilizing a point-of-care test. Future work will investigate whether this test can assist physicians in predicting amenability of burn wounds to autografting.

Meeting held at Henry Ford Hospital, Detroit, Michigan, in November 2017; International audience; In November 2017, a formal debate on the role of bacteria in the pathogenesis of hidradenitis suppurativa (HS) was held at the 2nd Symposium on Hidradenitis Suppurativa Advances (SHSA) in Detroit, Michigan. In this report, we present both sides of the argument as debated at the SHSA meeting and then discuss the potential role of bacteria as classic infectious pathogens versus an alternative pathogenic role as activators of dysregulated commensal bacterial-host interactions. Although there was consensus that bacteria play a role in pathogenesis and thus are pathogenic, there was a compelling discussion about whether bacteria in HS incite an infectious disease as we classically understand it or whether bacteria might play a different role in HS pathogenesis.

Multiuse eye drops must maintain sterility and typically accomplish this by added preservatives. However, preservatives often cause harmful side effects. A gauze barrier dressing ("BIOGUARDTo determine immobilized p-DADMAC's microbicidal efficacy, it was added to eye drop bottles, then contaminated with Staphylococcus aureus (SA113) bacteria. To assess interference with AI in eye drops, high performance liquid chromatography was used to determine whether the AIs timolol and dorzolamide were affected after exposure to p-DADMAC. To further investigate effects on AI, the microbicidal activity of VigamoxS. aureus bacteria were eliminated by p-DADMAC-treated gauze for all samples. The concentrations of both timolol and dorzolamide increased after exposure to p-DADMAC-treated gauze, but spectrometric analysis showed that this did not occur when the p-DADMAC-coated material was presoaked in deionized water. The microbicidial activity of moxifloxacin was unaffected by exposure to p-DADMAC-treated gauze.Due to its lack of effect on eye drop AI and its microbicidal efficacy, p-DADMAC treatment would make an excellent candidate for replacing preservatives in eye drops.

Hidradenitis suppurativa (HS) is a chronic skin disease of the pilo-sebaceous apocrine unit characterized by significant inflammation and an impaired quality of life. The pathogenesis of HS remains unclear. To determine the HS skin and blood transcriptomes and HS blood proteome, patient data from previously published studies were analysed and integrated from a cohort of patients with moderate to severe HS (n = 17) compared to healthy volunteers (n = 10). The analysis utilized empirical Bayes methods to determine differentially expressed genes (DEGs) (fold change (FCH) >2.0 and false discovery rate (FDR) 1.5, FDR

During herpes simplex virus (HSV) latency, most viral genes are silenced, with the exception of one region of the genome encoding the latency-associated transcript (LAT). This long noncoding RNA was originally described as having a role in enhancing HSV-1 reactivation. However, subsequent evidence showing that the LAT blocked apoptosis and promoted efficient establishment of latency suggested that its effects on reactivation were secondary to establishment. Here, we utilized an adeno-associated virus (AAV) vector to deliver a LAT-targeting hammerhead ribozyme to HSV-1-infected neurons of rabbits after the establishment of HSV-1 latency. The rabbits were then induced to reactivate latent HSV-1. Using this model, we show that decreasing LAT levels in neurons following the establishment of latency reduced the ability of the virus to reactivate. This demonstrates that the HSV-1 LAT RNA has a role in reactivation that is independent of its function in establishment of latency. In addition, these results suggest the potential of AAV vectors expressing LAT-targeting ribozymes as a potential therapy for recurrent HSV disease such as herpes stromal keratitis, a leading cause of infectious blindness.IMPORTANCE Herpes simplex virus (HSV) establishes a lifelong infection and remains dormant (latent) in our nerve cells. Occasionally HSV reactivates to cause disease, with HSV-1 typically causing cold sores whereas HSV-2 is the most common cause of genital herpes. The details of how HSV reactivates are largely unknown. Most of HSV's genes are silent during latency, with the exception of RNAs made from the latency-associated transcript (LAT) region. While viruses that make less LAT do not reactivate efficiently, these viruses also do not establish latency as efficiently. Here we deliver a ribozyme that can degrade the LAT to the nerve cells of latently infected rabbits using a gene therapy vector. We show that this treatment blocks reactivation in the majority of the rabbits. This work shows that the LAT RNA is important for reactivation and suggests the potential of this treatment as a therapy for treating HSV infections.

For proper wound healing, control of bacteria or bacterial infections is of major importance. While caring for a wound, dressing material plays a key role as bacteria can live in the bandage and keep re-infecting the wound. They do this by forming biofilms in the bandage, which slough off planktonic bacteria and overwhelm the host defense. It is thus necessary to develop a wound dressing that will inhibit bacterial growth. This study examines the effectiveness of a polyurethane foam wound dressing bound with polydiallyl-dimethylammonium chloride (pDADMAC) to inhibit the growth of bacteria in a wound on the back of a mouse. This technology does not allow pDADMAC to leach away from the dressing into the wound, thereby preventing cytotoxic effects. Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii were chosen for the study to infect the wounds. S. aureus and P. aeruginosa are important pathogens in wound infections, while A. baumannii was selected because of its ability to acquire or upregulate antibiotic drug resistance determinants. In addition, two different isolates of methicillin-resistant S. aureus (MRSA) were tested. All the bacteria were measured in the wound dressing and in the wound tissue under the dressing. Using colony-forming unit (CFU) assays, over six logs of inhibition (100%) were found for all the bacterial strains using pDADMAC-treated wound dressing when compared with control-untreated dressing. The CFU assay results obtained with the tissues were significant as there were 4-5 logs of reduction (100%) of the test organism in the tissue of the pDADMAC-covered wound versus that of the control dressing-covered wound. As the pDADMAC cannot leave the dressing (like other antimicrobials), this would imply that the dressing acts as a reservoir for free bacteria from a biofilm and plays a significant role in the development of a wound infection.

Connective tissue growth factor (CTGF) is a matricellular protein that mediates cell-matrix interaction through various subtypes of integrin receptors. This study investigated the role of CTGF and integrin αvβ6 in hepatic progenitor/oval cell activation, which often occurs in the form of ductular reactions (DRs) when hepatocyte proliferation is inhibited during severe liver injury. CTGF and integrin αvβ6 proteins were highly expressed in DRs of human cirrhotic livers and cholangiocarcinoma. Confocal microscopy analysis of livers from Ctgf promoter-driven green fluorescent protein reporter mice suggested that oval cells and cholangiocytes were the main sources of CTGF and integrin αvβ6 during liver injury induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Deletion of exon 4 of the Ctgf gene using tamoxifen-inducible Cre-loxP system down-regulated integrin αvβ6 in DDC-damaged livers of knockout mice. Ctgf deficiency or inhibition of integrin αvβ6, by administrating the neutralizing antibody, 6.3G9 (10 mg/kg body weight), caused low levels of epithelial cell adhesion molecule and cytokeratin 19 gene messenger RNAs. Also, there were smaller oval cell areas, fewer proliferating ductular epithelial cells, and lower cholestasis serum markers within 2 weeks after DDC treatment. Associated fibrosis was attenuated, as indicated by reduced expression of fibrosis-related genes, smaller areas of alpha-smooth muscle actin staining, and low collagen production based on hydroxyproline content and Sirius Red staining. Finally, integrin αvβ6 could bind to CTGF mediating oval cell adhesion to CTGF and fibronection substrata and promoting transforming growth factor (TGF)-β1 activation in vitro. Conclusions: CTGF and integrin αvβ6 regulate oval cell activation and fibrosis, probably through interacting with their common matrix and signal partners, fibronectin and TGF-β1. CTGF and integrin αvβ6 are potential therapeutic targets to control DRs and fibrosis in related liver disease. (Hepatology 2015;61:678-691)