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Venous leg ulcers affect approximately 1% of the general population and 3.6% of those over the age of 65. The goal of the research described herein is to shorten the time to healing by developing wound care alternatives that are based on a comprehensive understanding of the venous ulcer wound environment. The proteolytic and inflammatory components in wound fluids and tissue biopsy samples were characterized in subjects with documented long-standing venous ulcers that had showed resistance to standard therapy. All wounds showed polymicrobial colonization with greater than 106 CFU/g. Myeloperoxidase, a measure of leukocyte infiltration, was also markedly elevated in these wounds. Zymography revealed the presence of both pro-matrix metalloproteinase (MMP)-2 and pro-MMP-9 in wound fluids and to a lesser extent in tissue biopsies. Using an immunocapture activity assay we reveal a sevenfold excess of MMP-9 in wound fluid as compared to tissue, with 73% in the activated form. In contrast, MMP-8 total protein levels were nearly equal in wound fluids and biopsies. Fibronectin, a critical component of the extracellular matrix, was shown to be degraded in both wound fluids and biopsy samples. Finally, the potential of a novel wound dressing to neutralize several constituents of this hostile wound environment is shown. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a rare, painful neutrophilic dermatosis characterized by rapidly progressing skin ulcers. Despite the importance of local wound care in managing PG, there is no consensus or evidence-based guidelines. This systematic review aimed to investigate local wound care strategies for PG. A comprehensive search of Embase, MEDLINE, and the Cochrane Library yielded 1213 references, from which 269 studies were included, covering 351 patients. The most reported treatment methods included sharp debridement (11%), topical corticosteroids (27%) and non-adherent dressings (12%). However, no clear correlation between these treatments and healing outcomes was found likely due to confounding factors such as varied wound sizes, superinfection and inconsistent reporting. Additionally, directed wound care regimens have not been able to show statistical significance for healing outcomes. Our study describes the current local wound care landscape and underscores a critical gap in the current literature regarding standardized treatment protocols for PG., (© 2024 The Author(s). International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: The National Health Service (NHS) is suffering from a workforce crisis of mental and physical sickness and attrition following the COVID-19 pandemic. An in-depth understanding of healthcare workers' (HCWs) experiences during the pandemic is required to understand the impacts on their mental health in this challenging work environment. This qualitative study explores HCWs' concerns during the COVID-19 pandemic-expressed in real time during an active mental health crisis., Design: This study involved analysis of data from 'Shout', a text message-based, UK-wide mental health support service which, during the pandemic, was advertised to HCWs specifically. Pseudorandom sampling of scripts of anonymised text message conversations between HCWs and Shout Volunteers from April 2020 to March 2021 was undertaken, with data fully anonymised by Shout before researchers accessed them on a secure purpose-built platform. Following application of exclusion and inclusion criteria, 60 conversations were coded to develop a thematic framework and analysed using grounded theory, with subthemes triangulated to create final themes. Quotes extracted from this process were then synthesised for publication., Results: Three themes emerged from the data: (1) poor mental health, subthemes-(a) overwhelming negative feelings or emotional distress experienced, and; (b) active crisis/resurgent symptoms. (2) Negative work experiences, subthemes: (a) negative NHS work culture and expectations; (b) inadequate structures and arrangements for support; (c) trauma at work, and (d) abuse at work. (3) The impact of the COVID-19 pandemic, subthemes: (a) additional work pressure and (b) isolation and risk., Conclusion: This study explores the challenges and mental health concerns in HCWs during an active crisis. Organisational stressors, mental health provision and additional resources for HCWs to recover from the pandemic remain a vital issue in current NHS service provision., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-healing wounds are particularly prevalent in older adults and in patients with multiple comorbidities and represent a significant medico-economic burden. Autologous split-thickness skin grafts (STSG) are considered the gold standard for wound closure but suffer from high failure rates and complications. Autologous skin cell-suspension (ASCS) technology is an autografting technique able to significantly minimize donor site morbidity. This retrospective, propensity-matched cohort study compared outcomes of wounds treated with ASCS versus STSG., Study Design: Seven patients treated with ASCS were propensity-matched to 7 control patients who received STSG according to age and gender. The ASCS was prepared using the RECELL System and applied either alone as spray only ("ASCS alone", off-label) or combined with a widely meshed STSG ("ASCS+STSG", 3:1). The primary outcome was time to complete wound healing. Secondary outcomes included donor site healing, pain, and total number of visits. Statistical analyses included descriptive statistics, univariate analyses, and mixed-effect regression modeling to assess the impact of treatment on wound healing., Results: A total of 14 patients and 17 wounds (10 treatment vs 7 control) were included. Demographics were well-matched between cohorts. The overall mean wound healing time was 85.6±11.2 days. Wounds treated with ASCS (both ASCS groups) healed faster than STSG (75.9±4.5 vs 99.4±26.7 days). Wounds treated with ASCS alone healed in 80.8±5.1 days, while those treated with ASCS and STSG healed in 68.5±7.6 days., Conclusions: This study suggests ASCS may offer clinically significant improvements in wound and donor site healing, with significantly less donor skin requirements, and comparable pain levels, compared to traditional STSG. Further research with a prospective study and larger sample size is needed to validate these findings., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Preclinical studies for wound healing disorders are an essential step in translating discoveries into therapies. Also, they are an integral component of initial safety screening and gaining mechanistic insights using an in vivo approach. Given the complexity of the wound healing process, existing guidelines for animal testing do not capture key information due to the inevitable variability in experimental design. Variations in study interpretation are increased by complexities associated with wound aetiology, wounding procedure, multiple treatment conditions, wound assessment, and analysis, as well as lack of acknowledgement of limitation of the model used. Yet, no standards exist to guide reporting crucial experimental information required to interpret results in translational studies of wound healing. Consistency in reporting allows transparency, comparative, and meta-analysis studies and avoids repetition and redundancy. Therefore, there is a critical and unmet need to standardise reporting for preclinical wound studies. To aid in reporting experimental conditions, The Wound Reporting in Animal and Human Preclinical Studies (WRAHPS) Guidelines have now been created by the authors working with the Wound Care Collaborative Community (WCCC) GAPS group to provide a checklist and reporting template for the most frequently used preclinical models in support of development for human clinical trials for wound healing disorders. It is anticipated that the WRAHPS Guidelines will standardise comprehensive methods for reporting in scientific manuscripts and the wound healing field overall. This article is not intended to address regulatory requirements but is intended to provide general guidelines on important scientific considerations for such studies., (© 2024 The Author(s). Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions., Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906., Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], -5.3 [5.2] versus -6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): -2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], -19.5 [26.9] versus -32.2 [38.5]; least squares mean difference, 11.5 [96% CI: -4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group., Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group., Funding: Funded by Sanifit, a CSL Vifor company., Competing Interests: SS received consulting fees from Sanifit and Inozyme Pharma Inc; honoraria from AstraZeneca, Bayer, Sanofi-Genzyme, Novartis, CSL Vifor, GSK, Menarini, Medscape, and Boehringer-Ingelheim; support for attending meetings and/or travel from Sanifit, AstraZeneca, Novartis, and CSL Vifor. SUN received research funding to institution from Laboratoris Sanifit, CSL/Vifor, Hope Pharma, Inozyme Pharma, Epizon; consulting fees from Laboratoris Sanifit, CSL/Vifor, Inozyme Pharma, and Epizon; medical writing support from Laboratoris Sanifit and CSL/Vifor; royalties from UpToDate; and support for attending meetings and/or travel from Inozyme Pharma. LJG received consulting fees from Sanifit Therapeutics. SMM received consulting fees from Ardelyx, Sanfit, and Inozyme; and holds stock or stock options in Eli Lilly. DKC is an employee of Fresenius Medical Care and declares spousal stock in Amgen. KJC received consulting fees from Sanifit srl and Vifor Pharma. GA is an employee of CSL Vifor. LHK was an employee of and received stock compensation from CSL Vifor during the study. JP received consulting fees and stocks or stock options from Sanifit Therapeutics, which owns or has rights on patents related to this work where JP is a coinventor. AG was an employee of Sanifit Therapeutics and CSL Vifor and received consulting fees from Sanifit Therapeutics and CSL Vifor. GMC received graphics support (no writing support) from Sanifit, Vifor, and CSL Behring; received consulting fees from Sanifit, Akebia, AstraZeneca, CSL Behring, and Vertex; participated on a data safety monitoring board or Advisory Board for Ardelyx, Calico, and Miromatrix; served in a leadership or fiduciary role for Satellite Healthcare; received stock or stock options from CloudCath, Duract, Eliaz Therapeutics Outset, Renibus, and Unicycive. All other authors declare no competing interests., (© 2024 The Authors.)

The physical, emotional, and financial toll of acute and chronic nonhealing wounds on older adults and their caregivers is immense. Surgical treatment of wounds in older adults can facilitate healing but must consider the medical complexity of the patient, the patient's desires for treatment and the likelihood of healing. Innovative approaches and devices can promote rapid healing. By using a team approach, from preoperative planning to postoperative care, with a focus on the needs and desires of the patient, successful outcomes with improved patient satisfaction are possible even in medically complex patients., Competing Interests: Disclosure The author has received no funding and declares no conflicts of interest associated with this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

At present, there are no standardized guidelines for determining patient eligibility for pyoderma gangrenosum (PG) clinical trials. Thus, we aim to determine which clinical features, histopathological features, or laboratory features should be included in active ulcerative PG clinical trial eligibility criteria for treatment-naïve patients and patients already treated with immunomodulating medications (treatment-exposed patients). This study employed 4 rounds of the Delphi technique. Electronic surveys were administered to 21 international board-certified dermatologists and plastic surgeon PG experts (June 2022-December 2022). Our results demonstrated that for a patient to be eligible for a PG trial, they must meet the following criteria: (i) presence of ulcer(s) with erythematous/violaceous undermining wound borders, (ii) presence of a painful or tender ulcer, (iii) history/presence of rapidly progressing disease, (iv) exclusion of infection and other causes of cutaneous ulceration, (v) biopsy for H&E staining, and (vi) a presence/history of pathergy. These criteria vary in importance for treatment-naïve versus treatment-exposed patients. Given the international cohort, we were unable to facilitate live discussions between rounds. This Delphi consensus study provides a set of specific, standardized eligibility criteria for PG clinical trials, thus addressing one of the main issues hampering progress toward Food and Drug Administration approval of medications for PG., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition., Objectives: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG., Methods: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives., Results: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings., Conclusions: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS., Competing Interests: Conflicts of interest M.E.J. reports membership of the Harmonising Outcomes Measures for Eczema (HOME) Executive Committee. L.A.A.G. reports membership of the HOME Executive Committee and membership of the board of directors of the CHORD COUSIN Collaboration (C3). A.V.M. reports consultancy/advisory boards disease-relevant honoraria from AbbVie, Boehringer-Ingelheim, Novartis, Pfizer, Sanofi and UCB. D.M.C. reports employment with Genentech. J.D. reports consultations, lectures and/or studies for Aurealis, B. Braun, Biomonde, Coloplast, Convatec, Draco, Engelhardt, Flen Pharma, Lohmann & Rauscher, Mölnlycke, Smith & Nephew and Urgo; and also reports membership of the board of the following professional societies: Initiative Chronische Wunden, AG Wunde of the German Society of Dermatology, WundDACH. K.S.T. reports membership of the HOME Executive Committee and membership of the methods group for C3. A.G.O.-L. reports consultancy/advisory boards disease-relevant honoraria from Genentech, Boehringer-Ingelheim, Bristol Meyers Squibb and Janssen; reports research grants from Lilly, Pfizer and Janssen; and is also supported by NIAMS R01AR083110. J.W.R., W.B., L.J.G., D.L.O., T.Y., K.S., B.N. and D.L. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The major populations at risk for developing pressure ulcers are older adults who have multiple risk factors that increase their vulnerability, people who are critically ill and those with spinal cord injury/disease. The reported prevalence of pressure ulcers in the United States is 2.5 million. However, this estimate is derived from acute care facilities and does not include people who are living at home or in nursing facilities. Despite the implementation of hospital and facility-based preventive measures, the incidence of pressure ulcers has not decreased in decades. In addition to the burden of pain, infection and death, it is estimated that hospital-acquired pressure ulcers cost the health system $26.8 billion annually with over 50% of the cost attributed to treating Stage 3 and 4 pressure injuries. Thus, it is critical to examine the literature and develop guidelines that will improve the outcomes of this complex and costly condition. This guideline update is a compendium of the best available evidence for the treatment of Pressure Ulcers published since the last update in 2015 and includes a new section based on changing demographics entitled 'Palliative wound care for seriously ill patients with pressure ulcers'. The overall goal of the Wound Healing Society Guideline project is to present clear, concise and commercial free guidelines that clinicians can use to guide care, that researchers can use to develop studies that will improve treatment and that both clinicians and researchers can use to understand the gaps in our knowledge base., (© 2023 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Objective: Stage 3 and 4 pressure injuries (PIs) present an enormous societal burden with no clearly defined interventions for surgical reconstruction. The authors sought to assess, via literature review and a reflection/evaluation of their own clinical practice experience (where applicable), the current limitations to the surgical intervention of stage 3 or 4 PIs and propose an algorithm for surgical reconstruction., Methods: An interprofessional working group convened to review and assess the scientific literature and propose an algorithm for clinical practice. Data compiled from the literature and a comparison of institutional management were used to develop an algorithm for the surgical reconstruction of stage 3 and 4 PIs with adjunctive use of negative-pressure wound therapy and bioscaffolds., Results: Surgical reconstruction of PI has relatively high complication rates. The use of negative-pressure wound therapy as adjunctive therapy is beneficial and widespread, leading to reduced dressing change frequency. The evidence for the use of bioscaffolds both in standard wound care and as an adjunct to surgical reconstruction of PI is limited. The proposed algorithm aims to reduce complications typically seen with this patient cohort and improve patient outcomes from surgical intervention., Conclusions: The working group has proposed a surgical algorithm for stage 3 and 4 PI reconstruction. The algorithm will be validated and refined through additional clinical research., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that affects approximately 0.3-6 out of every 100,000 people worldwide. Clinical trials are scarce but there is growing interest in using newer and more targeted therapeutics to achieve disease remission. However, there are no standardized instruments to measure outcomes in PG and, therefore, future clinical trials are hampered by the absence of established and accurate means of assessment and comparison. Therefore, we aim to produce an internationally accepted core outcome set (COS) that will overcome this obstacle. This protocol outlines our intended approach to achieve the first part of this process, establishing a core outcome domain set., Methods: An international team of PG stakeholders, consisting of physicians, wound care nurses, patients, scientists and industry representatives, has been assembled for the purpose of building a comprehensive and universally established set of core outcome domains. During the first step, we will generate items of relevance using a nominal process from all stakeholders. Items will be distilled and collapsed into potential domains and subdomains. A systematic review of current methods for reporting PG has already been published and domains identified in this work will be considered in the generation of the core domains set. During the second step, after the potential domains and subdomains are identified, stakeholders will participate in an e-Delphi exercise to rate the importance of (sub)domains. A final consensus meeting will be organized with the goal of establishing a core domain set., Conclusion: Pyoderma gangrenosum lacks an established COS and previously published clinical trials have used inconsistent measures established from similarly inconsistent domains. As a first step this study seeks to create a core domain set within the COS, to build the foundation for future core outcome work for PG., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this paper, we review and analyze the commonly available wound healing models reported in the literature and discuss their advantages and issues, considering their relevance and translational potential to humans. Our analysis includes different in vitro and in silico as well as in vivo models and experimental techniques. We further explore the new technologies in the study of wound healing to provide an all encompassing review of the most efficient ways to proceed with wound healing experiments. We revealed that there is not one model of wound healing that is superior and can give translatable results to human research. Rather, there are many different models that have specific uses for studying certain processes or stages of wound healing. Our analysis suggests that when performing an experiment to assess stages of wound healing or different therapies to enhance healing, one must consider not only the species that will be used but also the type of model and how this can best replicate the physiology or pathophysiology in humans., Competing Interests: The authors declare the following competing financial interest(s): Morteza Mahmoudi discloses that (i) he is a co-founder and director of the Academic Parity Movement (www.paritymovement.org), a non-profit organization dedicated to addressing academic discrimination, violence and incivility; (ii) he is an advisor for and shareholder in Partners in Global Wound Care (PGWC), and a co-founder of and shareholder in NanoServ Corp. and Targets’ Tip Corp.; and (iii) he receives royalties/honoraria for his published books, plenary lectures, and licensed patent., (© 2023 American Chemical Society.)

This study assesses the impact of a processed microvascular tissue (PMVT) allograft on wound closure and healing in a prospective, single-blinded, multi-centre, randomised controlled clinical trial of 100 subjects with Wagner Grade 1 and 2 chronic neuropathic diabetic foot ulcerations. In addition to standard wound care, including standardised offloading, the treatment arm received PMVT while the control arm received a collagen alginate dressing. The primary endpoint was complete wound closure at 12 weeks. Secondary endpoints assessed on all subjects were percent wound area reduction, time to healing, and local neuropathy. Novel exploratory sub-studies were conducted for wound area perfusion and changes in regional neuropathy. Weekly application of PMVT resulted in increased complete wound closure at 12 weeks (74% vs 38%; P = .0003), greater percent wound area reduction from weeks four through 12 (76% vs 24%; P = .009), decreased time to healing (54 days vs 64 days; P = .009), and improved local neuropathy (118% vs 11%; P = .028) compared with the control arm. Enhanced perfusion and improved regional neuropathy were demonstrated in the sub-studies. In conclusion, this study demonstrated increased complete healing with PMVT and supports its use in treating non-healing DFUs. The observed benefit of PMVT on the exploratory regional neuropathy and perfusion endpoints warrants further study., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

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., (© 2022 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Background: Calcific uraemic arteriolopathy (CUA; calciphylaxis) is a rare disease seen predominantly in patients receiving dialysis. Calciphylaxis is characterized by poorly healing or non-healing wounds, and is associated with mortality, substantial morbidity related to infection and typically severe pain. In an open-label Phase 2 clinical trial, SNF472, a selective inhibitor of vascular calcification, was well-tolerated and associated with improvement in wound healing, reduction of wound-related pain and improvement in wound-related quality of life (QoL). Those results informed the design of the CALCIPHYX trial, an ongoing, randomized, placebo-controlled, Phase 3 trial of SNF472 for treatment of calciphylaxis., Methods: In CALCIPHYX, 66 patients receiving haemodialysis who have an ulcerated calciphylaxis lesion will be randomized 1:1 to double-blind SNF472 (7 mg/kg intravenously) or placebo three times weekly for 12 weeks (Part 1), then receive open-label SNF472 for 12 weeks (Part 2). All patients will receive stable background care, which may include pain medications and sodium thiosulphate, in accordance with the clinical practices of each site. A statistically significant difference between the SNF472 and placebo groups for improvement of either primary endpoint at Week 12 will demonstrate efficacy of SNF472: change in Bates-Jensen Wound Assessment Tool-CUA (a quantitative wound assessment tool for evaluating calciphylaxis lesions) or change in pain visual analogue scale score. Additional endpoints will address wound-related QoL, qualitative changes in wounds, wound size, analgesic use and safety., Conclusions: This randomized, placebo-controlled Phase 3 clinical trial will examine the efficacy and safety of SNF472 in patients who have ulcerated calciphylaxis lesions. Patient recruitment is ongoing., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Calcific uremic arteriolopathy (CUA; calciphylaxis) is a severe form of vascular calcification with no approved therapies. A standardized wound assessment tool is needed to evaluate changes in calciphylaxis wounds over time. A prospective, single-arm study of 14 patients with calciphylaxis reported improvement for the primary endpoint of wound healing using the 13-item Bates-Jensen Wound Assessment Tool (BWAT), although that tool was developed for assessment of pressure ulcers. This report describes development of BWAT-CUA, an 8-item modification of BWAT focusing on prototypical features of calciphylaxis lesions. The BWAT-CUA has a range of 8 (best) to 40 (worst) and was used ad hoc to analyze BWAT data collected in the prospective study. Using BWAT-CUA, relative improvement in calciphylaxis wounds was 30% overall (from 21.2 to 14.9; p = 0.0016) and 34% in the subset of 12 patients with ulceration at baseline (from 23.3 to 15.3; p = 0.0002). BWAT-CUA is a primary endpoint in an ongoing randomized, placebo-controlled phase 3 study of SNF472 recruiting patients with end-stage kidney disease and at least one ulcerated calciphylaxis lesion. BWAT-CUA, a newly developed tool for assessment of calciphylaxis wound severity and improvements over time, may be used in clinical research and in clinical practice.

The 2006 U.S. Food and Drug Administration Guidance for Industry emphasizes wound closure as the primary outcome for clinical trials in wound healing. Wound care professionals understand that complete wound healing is not always achievable when evaluating new treatments. FDA, Association for the Advancement of Wound Care, and Wound Healing Society are working collaboratively to identify scientifically achievable, clinically relevant, and patient-centered endpoints with sufficient support to serve as primary outcomes for clinical trials. The Opinion Survey from People with Wounds presented here addresses an important but understudied issue: the gap between clinician, healthcare insurance companies, government agencies, and patient perspectives regarding clinically meaningful and scientifically achievable primary endpoints for wound care. The survey, adapted from the clinician survey with adjustment for health literacy, was pilot tested and revised based on a limited number of patients in a single clinic. After central IRB approval, the on-line survey was administered in English and Spanish and submitted anonymously to a server with the cooperation of multiple wound clinics and societies. Four hundred and thirty-eight patients and caregivers from across the United States responded over a 10-month period. Based on this survey, the most valuable clinical endpoints were reduced infection, recurrence, and amputation. The most valuable quality of life outcomes were increased independence, reduced social isolation, and pain. The top five endpoints in terms of usefulness for measuring clinical trial success were time to heal, wound size, infection, recurrence, and pain. Narrative responses from wound patients emphasized the inability to perform activities of daily living and pain as major factors that impacted their daily lives. Engagement of patients in clinical trials and evaluation of potential treatments is critical to improving wound care. This survey provides insight into the needs of patients with wounds and provides a roadmap for structuring future clinical trials to better meet those needs., (© 2020 The Wound Healing Society.)

Objective: Chronic wounds are long-term nonhealing wounds that are refractory to treatment. These wounds can present elevated protease levels, leading to rapid degradation of native and exogenously added growth factors. This work focused on developing a protease-resistant growth factor formulation for treatment of chronic wounds presented with high protease activity. Approach: This study developed protease-resistant growth factor formulations comprising elastin-like peptides (ELPs) fused with a known protease inhibitor peptide or growth factor. The ELP component of the fusion proteins allows assembly of heterogeneous nanoparticles (NPs) putting the inhibitor in close proximity to the growth factor to be protected. Results: We show successful preservation of growth factor activity in high human neutrophil elastase (HNE) environment and in human chronic wound fluid derived from patients. We further show that these NPs result in enhanced collagen remodeling and resolution of inflammation in a full thickness wound supplemented with HNE in genetically diabetic mice. Innovation: Development of heterogeneous NPs that put the protease inhibitor in close proximity of the growth factor. Moreover, the modular nature of the NPs allows for protection of multiple growth factors by the same inhibitor without changing the amino acid sequence of the growth factor. Conclusion: Our results indicate that the developed NPs hold tremendous promise in chronic wound healing therapy and may further help the translation of growth factor therapies to clinic. The customizable template for the NP design allows for multifaceted use across several fields in research and medicine.

Pressure ulcers (PrUs) affect approximately 2.5 million patients and account for 60,000 deaths annually. They are associated with an additional annual cost of $43,000 per related hospital stay and a total cost to the US health care system as high as $25 billion. Despite the implementation of national and international PrU prevention guidelines and toolkits, rates of facility-acquired PrU s and PrUs in people with spinal cord injury are still high. A new paradigm is needed that distinguishes between prevention and treatment research methods and includes not only the causative factors of pressure and tissue deformation but also patient-specific anatomical differences and the concomitant biological cellular processes, including reperfusion injury, toxic metabolites, ischemia, cell distortion, impaired lymphatic drainage, and impaired interstitial fluid flow that compound existing tissue damage. The purpose of this article is to summarize the highlights from the first annual Pressure Ulcer Summit held February 9-10, 2018 in Atlanta, Georgia (sponsored by the Association for the Advancement of Wound Care in partnership with multiple professional organizations). This international, interdisciplinary summit brought together key stakeholders in wound care and PrU prevention and management to highlight advances in pathophysiology of pressure-induced tissue damage; explore challenges in current terminologies, documentation, and data collection; describe innovations in clinical care; and identify research opportunities to advance the science of PrU prevention and management., (© 2019 by the Wound Healing Society.)

Introduction: Microvascular tissue serves as the foundation for tissue granulation and remodeling during the wound healing process. Optimal repair of microvascular structure and function is essential for future healing capacity and to minimize tissue breakdown in a newly epithelialized wound., Objective: This case series of 3 patients with nonhealing diabetic foot ulcers (DFUs) refractory to standard wound care demonstrates the ability of processed microvascular tissue (PMVT) to enable wound closure, increase local perfusion and vascular maturity, and improve overall tissue quality., Materials and Methods: Three patients with nonhealing DFUs ranging from 1.1 cm2 to 11.2 cm2 recalcitrant to standard of care were treated weekly with topical PMVT and standard of care. Wound closure was measured weekly using infrared imaging. Fluorescence microangiography was used to perform dynamic quantification of wound microcirculation and assess the perfusion quality. Ingress rates were measured at 5 defined rectangular regions of interest of the wound to evaluate inflammation and microvascular integrity., Results: All 3 nonhealing DFUs treated with weekly topical PMVT healed within 12 weeks (average, 6.3 ± 5.5 weeks). Assessment of healed wounds at the time of closure indicated PMVT treatment significantly improved perfusion within the newly healed wounded area and throughout the immediate surrounding tissues. No wound recurrence or tissue deterioration has been observed in more than 9 months of follow-up., Conclusions: In this series of patients, the PMVT graft demonstrated improved wound closure, increased local perfusion and vascular maturity, and improved tissue quality. This graft is a promising advanced tissue therapy for nonhealing DFUs and other complex wounds. It is now the subject of a randomized controlled trial.

Use of ultra-portable, mechanically powered disposable negative pressure wound therapy (dNPWT) has grown as an adjunctive modality to manage wounds in outpatient care and to expedite transition of inpatients to an outpatient setting. This technology has demonstrated similar efficacy and usability for mobile outpatients when compared with electrically powered negative pressure wound therapy devices. It was designed for patients with smaller, low to moderately exudating wounds and does not require batteries or a power source. However, very few studies address best practices for using dNPWT in a variety of wound types. There is a need for comprehensive clinical recommendations to better direct clinicians and patients in using this therapy. In addition, it is critical that providers are knowledgeable about processes for obtaining reimbursement for placement of dNPWT since codes and procedures differ drastically from standard NPWT. A panel meeting of experts with a high level of experience with dNPWT in varied wound types was convened to develop clinical recommendations and summarize current US reimbursement coding guidelines for the use of dNPWT. This publication summarizes the recommendations from panel members, in addition to supporting evidence, to help guide appropriate use of dNPWT. Panel recommendations regarding optimal patient and wound selection, wound preparation, proper patient training, and use of dNPWT in various wound types are included as well as clinical techniques for dressing application, bridging under offloading devices and compression, maintaining a seal, and protecting intact skin. Processes and codes for obtaining reimbursement for dNPWT are reviewed by care setting. Clinical recommendations and reimbursement guidelines summarized in this publication are meant to provide direction to clinicians in using dNPWT that potentially could translate into improved clinical and economic value.

Patients with wounds bear significant clinical, personal, and economic burdens yet complete wound healing is the only United States Food and Drug Administration (FDA) recognized primary clinical trial end point. The overall goal of this project is to work with FDA to expand the list of acceptable primary end points, recognizing that new and innovative treatments, devices, and drugs may not have complete healing as the focus. Part 1 of the project surveyed 628 wound care experts who identified and content-validated 15 end points most relevant to clinical practice and benefitting patients' lives as primary outcomes in clinical trials. Part 2 is focused on critical appraisal of the evidence in the wound care literature supporting FDA criteria to qualify these 15 end points as primary end points in clinical trials. Further research involved systematic review of the literature regarding the most promising end points. Forty volunteer, interdisciplinary, wound healing experts in fields related to the end points compiled evidence from systematic MEDLINE searches and society databases supporting the FDA criteria of reliability, clinical construct validity, capacity to detect concurrent or longitudinal change, and responder analysis. The search revealed 485 references involving over 462,000 subjects supporting FDA-required parameters for all 15 end points More than 50 references supported FDA-required parameters qualifying the following outcomes for use in clinical trials supporting interventions for FDA clearance: Pain reduction, Physical function and ambulation, Infection reduction, Time to heal, and Percent wound area reduction in 4-8 weeks. Among these, only Time to heal is currently recognized by the FDA as a primary wound outcome in clinical trials. These results suggest that wound science is already serving patients and professionals by improving these content-validated outcomes that merit regulatory consideration., (© 2018 by the Wound Healing Society.)

Objective: Chronically ill patients heal recalcitrant ulcerative wounds more slowly. Human adipose-derived stem cells (hADSCs) play an important role in tissue regeneration and exosomes secreted by hADSC contribute to their paracrine signaling. In addition to cytokines, lipids and growth factors, hADSC secrete mRNA, miRNA, and long noncoding (lnc) RNA into exosomes. In this study we examined the role of lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), an abundant lncRNA in exosomes from conditioned media (CM), on cell migration and ischemic wound healing. Approach: CM and isolated exosomes from hADSC were applied to human dermal fibroblast (HDF) in scratch assays and electric cell-substrate impedance sensing (ECIS) assays. CM was also applied to a rat model of ischemic wound healing and wound closure was followed. Results: CM stimulated cell migration of HDFs in vitro by 48%. CM stimulated the closure of ischemic wounds in a rat model 50% faster than unconditioned media. The depletion of MALAT1 in adipose-derived stem cell (ADSC) CM significantly reduced cell migration. Since MALAT1 is secreted into exosomes, a purified population of exosomes was applied to HDF where they enhanced cell migration in a similar manner to FGF-2 or basic fibroblast growth factor (bFGF) in ECIS wound healing assays. The uptake of exosomes by HDF was shown using dynasore, an inhibitor that blocks clathrin- and caveolin-dependent endocytosis. Depletion of MALAT1 in hADSC with antisense oligonucleotides resulted in exosomes without MALAT1 . These exosomes had an effect similar to the unconditioned, control media in ECIS assays. Innovation: Exosomes contain lncRNA MALAT1 and other factors that have the potential to stimulate HDF cell migration and angiogenesis involved in wound healing without applying stem cells to wounds. Conclusion: Our results show the potential of using topically applied ADSC-derived exosomes containing MALAT1 for treating ischemic wounds. This allows for harnessing the power of stem cell paracrine signaling capabilities without applying the cells.

Objective: Compassionate care continues to be a focus for national and international attention, but the existing evidence base lacks the experimental methodology necessary to guide the selection of effective interventions for practice. This study aimed to evaluate the Creating Learning Environments for Compassionate Care (CLECC) intervention in improving compassionate care., Setting: Ward nursing teams (clusters) in two English National Health Service hospitals randomised to intervention (n=4) or control (n=2). Intervention wards comprised two medicines for older people (MOPs) wards and two medical/surgical wards. Control wards were both MOPs., Participants: Data collected from 627 patients and 178 staff., Exclusion Criteria: reverse barrier nursed, critically ill, palliative or non-English speaking. All other patients and all nursing staff and Health Care Assistant HCAs were invited to participant, agency and bank staff were excluded., Intervention: CLECC, a workplace intervention focused on developing sustainable leadership and work-team practices to support the delivery of compassionate care., Control: No educational activity., Primary and Secondary Outcome Measures: Primary-Quality of Interaction Schedule (QuIS) for observed staff-patient interactions. Secondary-patient-reported evaluations of emotional care in hospital (PEECH); nurse-reported empathy (Jefferson Scale of Empathy)., Results: Trial proceeded as per protocol, randomisation was acceptable. Some but not all blinding strategies were successful. QuIS observations achieved 93% recruitment rate with 25% of patient sample cognitively impaired. At follow-up there were more total positive (78% vs 74%) and less total negative (8% vs 11%) QuIS ratings for intervention wards versus control wards. Sixty-three per cent of intervention ward patients scored lowest (ie, more negative) scores on PEECH connection subscale, versus 79% of control. This was not a statistically significant difference. No statistically significant differences in nursing empathy were observed., Conclusions: Use of experimental methods is feasible. The use of structured observation of staff-patient interaction quality is a promising outcome measure inclusive of hard to reach groups., Trial Registration Number: ISRCTN16789770., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation., (© 2017 by the Wound Healing Society.)

Background: In a complex health system, it is important to establish a systematic and data-driven approach to identifying needs. The Diabetes Clinical Community (DCC) of Johns Hopkins Medicine's Armstrong Institute for Patient Safety and Quality developed a gap analysis tool and process to establish the system's current state of inpatient diabetes care., Methods: The collectively developed tool assessed the following areas: program infrastructure; protocols, policies, and order sets; patient and health care professional education; and automated data access. For the purposes of this analysis, gaps were defined as those instances in which local resources, infrastructure, or processes demonstrated a variance against the current national evidence base or institutionally defined best practices., Results: Following the gap analysis, members of the DCC, in collaboration with health system leadership, met to identify priority areas in order to integrate and synergize diabetes care resources and efforts to enhance quality and reduce disparities in care across the system. Key gaps in care identified included lack of standardized glucose management policies, lack of standardized training of health care professionals in inpatient diabetes management, and lack of access to automated data collection and analysis. These results were used to gain resources to support collaborative diabetes health system initiatives and to successfully obtain federal research funding to develop and pilot a pragmatic diabetes educational intervention., Conclusion: At a health system level, the summary format of this gap analysis tool is an effective method to clearly identify disparities in care to focus efforts and resources to improve care delivery., (Copyright © 2016 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Background: Venous leg ulcers (VLUs) represent the most common ulcers of the lower extremity. VLUs are notorious for delayed and prolonged healing with high rates of recurrence. Most patients with VLUs also have significant comorbidities that interfere with primary wound healing. Thus, caring for patients with VLUs requires an interdisciplinary approach that addresses the abnormal venous anatomy and the downstream effects that lead to inflammation, ulceration, and a hostile wound microenvironment., Methods: The current literature regarding venous ulcer treatment with an emphasis on compression, surgical options, and use of bioengineered tissue was reviewed. A combination of society guidelines, Cochrane reviews, and over 80 primary articles with high-level evidence were utilized to develop this summary and algorithm for an integrated approach to treating patients with venous ulcers. Details regarding compression modalities and venous diagnostic imaging are presented to help the clinician understand the rationale for using these technologies., Results: The comprehensive approach to the patient with chronic venous insufficiency (CVI) includes advances in compression, diagnostics, minimally invasive surgical treatment of venous disease, wound bed preparation, and bioengineered skin and soft tissue substitutes. An algorithm that incorporates early treatment of the ulcer and the venous disease leading to healing with prevention of recurrence is presented., Conclusions: Utilizing guidelines that incorporate evidence-based modalities will lead to the highest quality outcomes with the most appropriate resource utilization. A proactive approach to treating venous disease will alleviate suffering and prevent the long-term sequelae of CVI.

Hyperbaric oxygen (HBO) therapy is a versatile modality that has applications across several medical fields. HBO therapy has become a valuable asset in the management of compromised tissue grafts and flaps. Although classified together, grafts and flaps are distinctly different, in that grafts depend on the wound bed for revascularization, whereas flaps have an inherent blood supply. Evidence has shown that in a compromised graft suffering from hypoxia, HBO can maximize viability and reduce the need for repeat grafting. By comparison, compromised flaps can suffer from both ischemic and reperfusion injury, which can also be attenuated by HBOT to maximize viability. The beneficial effects of HBO occur by several mechanisms, including hyper-oxygenation, fibroblast proliferation, collagen deposition, angiogenesis, and vasculogenesis. Animal studies have demonstrated several of these mechanisms, including an increase in the number, size, and growth distance of blood vessels after HBO. Likewise, clinical studies have found positive responses in multiple types of tissue grafts and flaps, with some cases involving irradiated fields. Altogether, the data emphasizes that early identification of flap or graft compromise is absolutely critical, with maximized chance for viability when HBO is initiated as soon as possible.

Impaired wound healing in the elderly represents a major clinical problem that is growing as our population ages. Wound healing is affected by age and by co-morbid conditions, particularly diabetes and obesity. This is particularly important in Rhode Island as the state has a very high percentage of vulnerable older adults. A multi- disciplinary approach that incorporates the skills of a comprehensive wound center with specialized nursing, geriatric medicine and palliative care will facilitate rapid wound healing, reduce costs and improve outcomes for our older adults that suffer from 'problem wounds'.

Significance: The extracellular matrix (ECM) is known to be deficient in chronic wounds. Collagen is the major protein in the ECM. Many claims are made while extolling the virtues of collagen-based biomaterials in promoting cell growth and modulating matrix metalloproteinases. This review will explore the rationale for using topical collagen or ECM as an interface for healing. Recent Advances: Rapid improvements in electrospinning and nanotechnology have resulted in the creation of third-generation biomaterials that mimic the native ECM, stimulate cellular and genetic responses in the target tissue, and provide a platform for controlled release of bioactive molecules and live cells. Although the major focus is currently on development of artificial tissues and organ regeneration, better understanding of the mechanisms that stimulate wound healing can be applied to specific deficits in the chronic wound. Critical Issues: When choosing between the various advanced wound-care products and dressings, the clinician is challenged to select the most appropriate material at the right time. Understanding how the ECM components promote tissue regeneration and modulate the wound microenvironment will facilitate those choices. Laboratory discoveries of biomolecular and cellular strategies that promote skin regeneration rather than repair should be demonstrated to translate to deficits in the chronic wound. Future Directions: Cost-effective production of materials that utilize non-mammalian sources of collagen or ECM components combined with synthetic scaffolding will provide an optimal structure for cellular ingrowth and modulation of the chronic wound microenvironment to facilitate healing. These bioengineered materials will be customizable to provide time-released delivery of bioactive molecules or drugs based on the degradation rate of the scaffold or specific signals from the wound.

Background: Clinical communities are an emerging approach to quality improvement (QI) to which several large-scale projects have attributed some success. In 2011 the Armstrong Institute for Patient Safety and Quality established clinical communities as a core strategy to connect frontline providers from six different hospitals to improve quality of care, patient safety, and value across the health system. CLINICAL COMMUNITIES: Fourteen clinical communities that presented great opportunity for improvement were established. A community could focus on a clinical area, a patient population, a group, a process, a safety-related issue, or nearly any health care issue. The collaborative spirit of the communities embraced interdisciplinary membership and representation from each hospital in each community. Communities engaged in team-building activities and facilitated discussions, met monthly, and were encouraged to meet in person to develop relationships and build trust. After a community was established, patients and families were invited to join and share their perspectives and experiences. ENABLING STRUCTURES: The clinical community structure provided clinicians access to resources, such as technical experts and safety and QI researchers, that were not easily otherwise accessible or available. Communities convened clinicians from each hospital to consider safety problems and their resolution and share learning with workplace peers and local unit safety teams., Conclusion: The clinical communities engaged 195 clinicians from across the health system in QI projects and peer learning. Challenges included limited financial support and time for clinicians, timely access to data, limited resources from the health system, and not enough time with improvement experts.

Background: Skin graft donor sites are notoriously painful, with potential complications of fluid loss, delayed healing, infection, and hypertrophic scarring, particularly in patients with burns or traumatic injury. In this population, rapid epithelialization is critical to reducing morbidity and cost., Study Design: This prospective, randomized controlled trial compared the effects of 40-kHz noncontact low-frequency ultrasound (NLFU) in addition to standard care (SC) with SC alone in subjects with split-thickness donor sites of 20 to 200 cm(2). Standard care consisted of cleansing and moist wound dressings. Outcomes measured were time to healing, defined as absence of drainage and full epithelialization; pain and itching scores; and recidivism rates., Results: Of 33 patients enrolled; 27 were randomized and received a minimum of 4 study treatments. Median age was 49 years, 69% were male, and 84% were burn patients. Comorbidities included hypertension (31%), coronary artery disease (22%), pulmonary disease (38%), anemia (31%), and diabetes (16%). Median donor site area was 136.0 cm(2). Noncontact low-frequency ultrasound and SC compared with SC demonstrated a mean time to heal of 12.1 days vs 21.3 days (p = 0.04). All NLFU+SC subjects had epithelialized by 4 weeks compared with only 71% in SC. Recidivism rates were 8% for NLFU+SC compared with 45% for SC. Pain scores were reduced and significant differences in itching were observed., Conclusions: Noncontact low-frequency ultrasound and SC compared with SC alone in the treatment of split-thickness donor sites demonstrated significant accelerated healing and reduced pain and itching. Noncontact low-frequency ultrasound subjects experienced a better quality of healing with less incidence of infection and recidivism., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The propensity for chronic wounds in humans increases with ageing, disease conditions such as diabetes and impaired cardiovascular function, and unrelieved pressure due to immobility. Animal models have been developed that attempt to mimic these conditions for the purpose of furthering our understanding of the complexity of chronic wounds. The model described herein is a rat ischemic skin flap model that permits a prolonged reduction of blood flow resulting in wounds that become ischemic and resemble a chronic wound phenotype (reduced vascularization, increased inflammation and delayed wound closure). It consists of a bipedicled dorsal flap with 2 ischemic wounds placed centrally and 2 non-ischemic wounds lateral to the flap as controls. A novel addition to this ischemic skin flap model is the placement of a silicone sheet beneath the flap that functions as a barrier and a splint to prevent revascularization and reduce contraction as the wounds heal. Despite the debate of using rats for wound healing studies due to their quite distinct anatomic and physiologic differences compared to humans (i.e., the presence of a panniculus carnosus muscle, short life-span, increased number of hair follicles, and their ability to heal infected wounds) the modifications employed in this model make it a valuable alternative to previously developed ischemic skin flap models.

Pressure ulcers are one of the most common causes of morbidity, mortality and rehospitalization for those living with Spinal Cord Injury (SCI). Literature examining risk and recurrence of pressure ulcers (PrUs) has primarily focused on the nursing home elderly who do not have SCI. More than 200 factors that increase PrU risk have been identified. Yet unlike the elderly who incur pressure ulcers in nursing homes or when hospitalized, most persons with SCI develop their pressure ulcers as outpatients, while residing in the community. The Veterans Health Administration (VHA) provides medical care for a large number of persons with chronic SCI. Included in the VHA SCI model of chronic disease management is the provision of an annual Comprehensive Preventive Health Evaluation, a tool that has potential to identify individuals at high risk for PrUs. This research was motivated by the clinical observation that some individuals appear to be protected from developing PrUs despite apparently 'risky' behaviors while others develop PrUs despite vigilant use of the currently known preventative measures. There is limited literature regarding protective factors and specific risk factors that reduce PrU occurrence in the community dwelling person with chronic SCI have not been delineated. The purpose of this study is to examine the preliminary hypothesis that there are biological and/or psychosocial factors that increase or reduce vulnerability to PrUs among persons with SCI. A limited number of refined hypotheses will be generated for testing in a prospective fashion. A retrospective cross-sectional survey of 119 randomly selected Veterans with SCI undergoing the Comprehensive Health Prevention Evaluation during the year 2009 was performed. Factors that differed between patients with 0, 1 or ⩾2 PrUs were identified and stratified, with an emphasis on modifiable risk factors. Three hypotheses generated from this study warrant further investigation: (1) cumulative smoking history increases the risk of PrUs independent of co-morbidities, (2) being moderately overweight, BMI>25, with or without spasticity, is a modifiable factor that may be protective and (3) increased use of a caregiver does not reduce PrU risk. Prospective studies that focus on these hypotheses will lead to evidence-based risk assessment tools and customized interventions to prevent PrUs in persons with SCI in the outpatient setting., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Lipid mediators derived from 5-lipoxygenase (5-LO) metabolism can activate both pro- and anti-inflammatory pathways, but their role in wound healing remains largely unexplored. In this study we show that 5-LO knockout (5-LO(-/-)) mice exhibited faster wound healing than wild-type (WT) animals, and exhibited upregulation of heme oxygenase-1 (HO-1). Furthermore, HO-1 inhibition in 5-LO(-/-) mice abolished the beneficial effect observed. Despite the fact that 5-LO(-/-) mice exhibited faster healing, in in vitro assays both migration and proliferation of human dermal fibroblasts (HDFs) were inhibited by the 5-LO pharmacologic inhibitor AA861. No changes were observed in the expression of fibronectin, transforming growth factor (I and III), and α-smooth muscle actin (α-SMA). Interestingly, AA861 treatment significantly decreased ROS formation by stimulated fibroblasts. Similar to 5-LO(-/-) mice, induction of HO-1, but not superoxide dismutase-2 (SOD-2), was also observed in response to 5-LO (AA861) or 5-LO activating protein (MK886) inhibitors. HO-1 induction was independent of nuclear factor (erythroid derived-2) like2 (Nrf-2), cyclooxygenase 2 (COX-2) products, or lipoxin action. Taken together, our results show that 5-LO disruption improves wound healing and alters fibroblast function by an antioxidant mechanism based on HO-1 induction. Overexpression of HO-1 in wounds may facilitate early wound resolution.

Advertisements targeted at the elderly population suggest that antioxidant therapy will reduce free radicals and promote wound healing, yet few scientific studies substantiate these claims. To better understand the potential utility of supplemental antioxidant therapy for wound healing, we tested the hypothesis that age and tissue ischemia alter the balance of endogenous antioxidant enzymes. Using a bipedicled skin flap model, ischemic and non-ischemic wounds were created on young and aged rats. Wound closure and the balance of the critical antioxidants superoxide dismutase and glutathione in the wound bed were determined. Ischemia delayed wound closure significantly more in aged rats. Lower superoxide dismutase 2 and glutathione in non-ischemic wounds of aged rats indicate a basal deficit due to age alone. Ischemic wounds from aged rats had lower superoxide dismutase 2 protein and activity initially, coupled with decreased ratios of reduced/oxidized glutathione and lower glutathione peroxidase activity. De novo glutathione synthesis, to restore redox balance in aged ischemic wounds, was initiated as evidenced by increased glutamate cysteine ligase. Results demonstrate deficiencies in two antioxidant pathways in aged rats that become exaggerated in ischemic tissue, culminating in profoundly impaired wound healing and prolonged inflammation.

A brief description of the Wound Recovery and Hyperbaric Medicine Center, now in its second decade of service, will inform the general medical community of this valuable asset. Demand for wound care services is predicted to grow steadily over the next several decades. Kent Hospital's vision for wound care is embodied in its thriving Wound Recovery and Hyperbaric Medicine Center. New cost- effective wound healing therapies must be developed and evidence-based practices established. New physicians and support staff must be trained. Only through a blending of high quality clinical care with research and education will these objectives be achieved and future successes in the management of patients and their wounds be made possible.

Objective: Adipose tissue is a robust source of adipose-derived stem cells (ADSCs) that may be able to provide secreted factors that promote the ability of wounded tissue to heal. However, adipocytes also have the potential to dedifferentiate in culture to cells with stem cell-like properties that may improve their behavior and functionality for certain applications. Approach: ADSCs are adult mesenchymal stem cells that are cultured from the stromal vascular fraction of adipose tissue. However, adipocytes are capable of dedifferentiating into cells with stem cell properties. In this case study, we compare ADSC and dedifferentiated fat (DFAT) cells from the same patient and fat depot for mesenchymal cell markers, embryonic stem cell markers, ability to differentiate to adipocytes and osteoblasts, senescence and telomerase levels, and ability of conditioned media (CM) to stimulate migration of human dermal fibroblasts (HDFs). Innovation and Conclusions: ADSCs and DFAT cells displayed identical levels of CD90, CD44, CD105, and were CD34- and CD45-negative. They also expressed similar levels of Oct4, BMI1, KLF4, and SALL4. DFAT cells, however, showed higher efficiency in adipogenic and osteogenic capacity. Telomerase levels of DFAT cells were double those of ADSCs, and senescence declined in DFAT cells. CM from both cell types altered the migration of fibroblasts. Despite reports of ADSCs from a number of human depots, there have been no comparisons of the ability of dedifferentiated DFAT cells from the same donor and depot to differentiate or modulate migration of HDFs. Since ADSCs were from an obese diabetic donor, reprogramming of DFAT cells may help improve a patient's cells for regenerative medicine applications.

Little is known about the impact of hyperbaric oxygen treatment (HBOT) on matrix metalloproteinase (MMP) production in pre-existing high-oxidant wounds. This study aimed to investigate whether HBOT modulates reactive oxygen species (ROS) and MMP regulation in ischemic wound tissue. Using a validated ischemic wound model, Sprague-Dawley rats were divided into four groups for daily treatment: HBOT, N-acetylcysteine (NAC), HBO and NAC, and control (normoxia at sea level). High levels of inducible nitric oxide synthase (iNOS), gp91-phox, and 3-nitrotyrosine were detected in ischemic wounds, indicating high-oxidant stress. HBOT not only increased antioxidant enzyme expression, such as Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase, but also significantly decreased pro-oxidant enzyme levels, such as iNOS and gp91-phox, thereby decreasing net oxygen radical production by means of negative feedback. This effect was blocked by NAC treatment in ischemic wounds. HBO-treated ischemic wounds also manifested reduced phosphorylation of extracellular signal-regulated kinases 1/2, c-Jun N-terminal kinase, and c-Jun, indicating downregulation of mitogen-activated protein kinases (MAPKs). Furthermore, HBOT decreased the expression of several MMPs while simultaneously increasing tissue inhibitor of MMP (tissue inhibitor of metalloproteinase 2). These results indicate that HBOT acts via the ROS/MAPK/MMP signaling axis to reduce tissue degeneration and improve ischemic wound healing.