William J. Ennis

Macrophage PPARγ and impaired wound healing in type 2 diabetes.

Macrophages undergo a transition from pro‐inflammatory to healing‐associated phenotypes that is critical for efficient wound healing. However, the regulation of this transition during normal and impaired healing remains to be elucidated. In our studies, the switch in macrophage phenotypes during skin wound healing was associated with up‐regulation of the peroxisome proliferator‐activated receptor (PPAR)γ and its downstream targets, along with increased mitochondrial content. In the setting of diabetes, up‐regulation of PPARγ activity was impaired by sustained expression of IL‐1β in both mouse and human wounds. In addition, experiments with myeloid‐specific PPARγ knockout mice indicated that loss of PPARγ in macrophages is sufficient to prolong wound inflammation and delay healing. Furthermore, PPARγ agonists promoted a healing‐associated macrophage phenotype both in vitro and in vivo, even in the diabetic wound environment. Importantly, topical administration of PPARγ agonists improved healing in diabetic mice, suggesting an appealing strategy for down‐regulating inflammation and improving the healing of chronic wounds. Copyright

Wound healing society 2015 update on guidelines for venous ulcers

The Wound Healing Society (WHS) guidelines for the treatment of venous ulcers were originally published in 2006. These guidelines provided recommendations, along with their respective levels of evidence and strength on various categories. Over the past 7 years, a great deal of literature regarding these aspects of venous ulcer management has been published. An advisory panel comprised of academicians, clinicians, and researchers was chosen to update the 2006 guidelines. Members included vascular surgeons, internists, plastic surgeons, anesthesiologists, dermatologists, emergency medicine physicians, and registered nurses, all with expertise in wound healing. The goal of this article is to evaluate relevant new findings, on which an updated version of the guidelines will be based.

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community

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.

Amniotic membrane is a potential regenerative option for chronic non‐healing wounds: a report of five cases receiving dehydrated human amnion/chorion membrane allograft

A case series of five patients with a total of six chronic non‐healing wounds (>30 day duration) were non‐randomly selected to evaluate the performance, safety and handling properties of dehydrated human amnion/chorion membrane allograft, an amniotic membrane scaffolding product. The patients had lower extremity wounds that had previously failed standard of care within a university outpatient/inpatient wound healing programme. Five wounds treated with dehydrated amnion/chorion membrane allograft showed a mean 43% area reduction from baseline (51% median) at 3 weeks into treatment and completely healed with a 64‐day median time to closure (SD ±27·6 days). One wound worsened at 3 weeks and was found to have a complete central vein obstruction that was treated with long‐term mild compression but still eventually healed at 6 months. Removing this outlier, the four responding wounds had a 72% mean and 69% median change in area from baseline, at the 3 week point. All five patients received only one application of dehydrated human amnion/chorion membrane allograft, and there were no adverse events. The product was easy to use, administer and handle. In summary, dehydrated human amnion/chorion membrane allograft appears to be a safe, effective and easy to use therapy for chronic non‐healing wounds. This study describes the details of these clinical cases and provides an overview of the current evidence on the use of amniotic tissue in clinical practice.

A treatment algorithm to identify therapeutic approaches for leg ulcers in patients with sickle cell disease.

Sickle cell leg ulcers (SCLUs) are a common complication of sickle cell disease (SCD). Patients who develop ulcers appear to have a more severe haemolysis‐associated vasculopathy than individuals who do not develop them, and manifest other complications such as priapism and pulmonary hypertension. SCLUs are slow to heal and often recur, affecting both the emotional and physical well‐being of patients. Here we summarise what is known about the pathophysiology of SCLUs, describe available treatment options and propose a treatment algorithm.

Wound healing outcomes: Using big data and a modified intent-to-treat method as a metric for reporting healing rates

Chronic wounds are increasing in prevalence and are a costly problem for the US healthcare system and throughout the world. Typically outcomes studies in the field of wound care have been limited to small clinical trials, comparative effectiveness cohorts and attempts to extrapolate results from claims databases. As a result, outcomes in real world clinical settings may differ from these published studies. This study presents a modified intent‐to‐treat framework for measuring wound outcomes and measures the consistency of population based outcomes across two distinct settings. In this retrospective observational analysis, we describe the largest to date, cohort of patient wound outcomes derived from 626 hospital based clinics and one academic tertiary care clinic. We present the results of a modified intent‐to‐treat analysis of wound outcomes as well as demographic and descriptive data. After applying the exclusion criteria, the final analytic sample includes the outcomes from 667,291 wounds in the national sample and 1,788 wounds in the academic sample. We found a consistent modified intent to treat healing rate of 74.6% from the 626 clinics and 77.6% in the academic center. We recommend that a standard modified intent to treat healing rate be used to report wound outcomes to allow for consistency and comparability in measurement across providers, payers and healthcare systems.

Wound Healing: A Comprehensive Wound Assessment and Treatment Approach

Wound healing is a complex process that requires the coordination of many interdependent steps. There have been many advances in the science of wound healing and numerous new techniques for treating wounds. The process of wound healing can be defined by the stages of hemostasis, inflammation, proliferation, epithelialization, and remodeling. There are many factors that can negatively impact the normal healing cascade, and these can be divided into local, systemic, and iatrogenic factors. The most common chronic wounds treated in wound centers include venous leg ulcers, diabetic foot ulcers, and pressure ulcers. Despite a potentially large number of different wound etiologies, the work-up of a patient with a nonhealing wound is very systematic, and a general approach can be taken with all patients. This chapter reviews the history, physiology, factors influencing, and future directions of chronic wound care. A diagnostic algorithm is described that will assist the clinician when presented with a patient with a nonhealing, chronic wound.

Combat Wound Initiative Program

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.

Ischemia/Reperfusion: A Potential Cause for Tissue Necrosis

There are many clinical conditions which are either caused or exacerbated by ischemia/reperfusion injury (IRI). While the wound care community has expanded its understanding of the cellular and molecular mechanisms surrounding the healing process, research involving the microcirculation and its impact on healing has been limited. Reasons for this include but are not limited to an emphasis on the diagnosis and treatment of macrovascular disorders, the absence of surgical options directed at the microcirculation, and a limited number of pharmacologic and/or modality-based therapeutic options. There are also few well-accepted methods for the diagnosis of adequate tissue perfusion, and those that are available have not been transferred well from the lab to the bedside. Clinicians are therefore left with their experience and macro-level observations as a primary means for gauging successful outcomes. Once macro-level changes are apparent, however, it is often too late to intervene therapeutically thus limiting the potential efficacy of treatment options. In this chapter, we will describe the basic anatomy and physiology of the microcirculation and then focus on the consequences, both positive and negative, of the restoration of flow to ischemic tissue. New potentially useful diagnostic methods for assessing tissue perfusion and microcirculation will be presented along with a clinical case that will bring these didactic concepts into a real-world clinical setting. Finally, new treatment options that may mitigate the effects of ischemic reperfusion injury will be discussed.

Erratum to: Skin Necrosis

Necrosis in burns has a major impact on dermal regeneration, functional, and esthetic results. Thus patient’s satisfaction and quality of life is determined by the timely regeneration process of all dermal layers. Pathophysiological changes after burn trauma lead to different perfusion patterns (“zones”). Inflammation has been described having a key role in maintaining reduced subdermal perfusion with increased risk of burn necrosis. In addition, various key regulators of inflammation have been identified to play a critical role in activating burn necrosis. This chapter analyzes the impact of necrosis in acute burns and gives an overview of the currently available literature of pathophysiology, apoptosis, and inflammation in burns resulting in primary, secondary, or tertiary burn necrosis. Local therapeutic options are discussed, but it is not intended to be exhaustive with regard to systemic reactions and systemic therapy in case of burn necrosis. In summary, there is increasing evidence of pathophysiology of necrosis in burns in animal models, but there is still a lack of transfer to clinical application.