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The incidence of chronic wounds is increased among older adults, and the impact of chronic wounds on quality of life is particularly profound in this population. It is well established that wound healing slows with age. However, the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The impact of age and accompanying multi-morbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables, lack of standardization in data collection, and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this paper, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify key research questions to guide future study of age-associated changes in chronic wound healing.

Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes in which bacterial presence, including the frequent colonizer Staphylococcus aureus, contributes to inhibition of healing. MicroRNAs (miRs) play a role in healing and host response to bacterial pathogens. However, the mechanisms by which miR response to cutaneous S. aureus contributes to DFU pathophysiology are unknown. Here, we show that S. aureus inhibits wound closure and induces miR-15b-5p in acute human and porcine wound models and in chronic DFUs. Transcriptome analyses of DFU tissue showed induction of miR-15b-5p to be critical, regulating many cellular processes, including DNA repair and inflammatory response, by suppressing downstream targets IKBKB, WEE1, FGF2, RAD50, MSH2, and KIT. Using a human wound model, we confirmed that S. aureus-triggered miR-15b-5p induction results in suppression of the inflammatory- and DNA repair-related genes IKBKB and WEE1. Inhibition of DNA repair and accumulation of DNA breaks was functionally confirmed by the presence of the pH2AX within colonized DFUs. We conclude that S. aureus induces miR-15b-5p, subsequently repressing DNA repair and inflammatory response, showing a mechanism of inhibition of healing in DFUs previously unreported, to our knowledge. This underscores a previously unknown role of DNA damage repair in the pathophysiology of DFUs colonized with S. aureus.

Diabetic foot ulcers (DFUs), a life-threatening complication of diabetes mellitus, have limited treatment options, often resulting in amputations. HMG-CoA reductase inhibitors such as statins are cholesterol-reducing agents that may provide a new therapeutic option. Statins target the cholesterol pathway and block the synthesis of the wound-healing inhibitors farnesyl pyrophosphate (FPP) and cortisol, ligands for the glucocorticoid receptor (GR). Here we demonstrate that the naturally occurring statin mevastatin reverses FPP's effects and promotes healing by using in vitro wound healing assays, human ex vivo and porcine in vivo wound models, and DFU tissue. Moreover, we measured cortisol levels by ELISA and found that mevastatin inhibited cortisol synthesis in keratinocytes and biopsies from patients with DFU. Of note, topical mevastatin stimulated epithelialization and angiogenesis in vivo. Mevastatin also reversed FPP-mediated induction of the GR target, the transcription factor c-Myc (a biomarker of non-healing wounds), in porcine and human wound models. Importantly, mevastatin reversed c-Myc overexpression in DFUs. It induced expression of the long noncoding RNA Gas5 that blocks c-Myc expression, which was confirmed by overexpression studies. We conclude that topical mevastatin accelerates wound closure by promoting epithelialization via multiple mechanisms: modulation of GR ligands and induction of the long noncoding RNA Gas5, leading to c-Myc inhibition. In light of these findings, we propose that repurposing statin drugs for topical treatment of DFUs may offer another option for managing this serious condition.

Wound care dressings have evolved over time, from bandaging to the development of occlusive dressings to negative pressure wound therapy. A novel therapeutic delivery system dressing has been cleared by the United States Food and Drug Administration. This semi occlusive wound dressing has been developed to provide local, continuous delivery of aqueous topical agents, such as therapeutics (anesthetics, antiseptics, antibiotics, steroids, topical beta-blockers, immune modulatory agents, growth factors, and fibrinolytic agents, among others), at a rate of about ¾ mL per day, thus maintaining a hydrated environment and providing topical treatment. This type of system may be beneficial in situations where systemic therapies cannot be used, wounds are small and few, wounds may need frequent application of medication or moisture, or low and steady delivery of medications is needed.The authors assessed a delivery system dressing with different types of liquid medications for the management of hard-to-heal, chronic lower extremity wounds.Patients aged ≥ 18 and ≤ 90 years with stalled chronic wounds30 days' duration were selected for the use of a topical delivery system, which consists of a semi occlusive wound dressing and fluid delivery unit that can provide local application of small therapeutic quantities of medication directly to the wound.Several successful cases with the use of this device are presented in which pain relief, enhancement of epithelial migration, inflammation reduction, bacterial control, and wound size reduction were achieved.This delivery system dressing is an effective and safe treatment option for wounds. Advantages include reduced potential of systemic side effects, flexibility in what can be delivered, constant rate of medication delivery, and convenience.

The flipped classroom module incorporates independent study in advance of in-class instructional sessions. It is unproven whether this methodology is effective within a medical school second-year organ system module. We report the development, implementation, and effectiveness of the flipped classroom methodology in a second-year medical student dermatology module at the University of Miami Leonard M. Miller School of Medicine.In a retrospective cohort analysis, we compared attitudinal survey data and mean scores for a 50-item multiple-choice final examination of the second-year medical students who participated in this 1-week flipped course with those of the previous year's traditional, lecture-based course.Each group comprised nearly 200 students. Students' age, sex, Medical College Admission Test scores, and undergraduate grade point averages were comparable between the flipped and traditional classroom students. The flipped module students' mean final examination score of 92.71% ± 5.03% was greater than that of the traditional module students' 90.92% ± 5.51% (The flipped classroom can be an effective instructional methodology for a medical school second-year organ system module.

The authors report a case of pretibial myxedema (PTM) masquerading as a venous leg ulcer to alert wound care clinicians to this diagnostic possibility. Pretibial myxedema is a localized form of mucin cutaneous deposition characterized by indurated plaques most commonly on anterior legs. It is more likely to present in patients with Graves' disease, but it can be found in euthyroid patients as well. The physiopathology of PTM is complex, and there is an accumulation of highly hydrophilic glycosaminoglycans in the dermis. Minimal morbidity is associated with PTM, but the pruritus related to mucin deposition can be intense. The skin around venous leg ulcers and the skin changes related to PTM can have a similar clinical presentation, which may be a reason PTM is under-recognized.

Non-thermal laser therapy in dermatology, is a growing field in medical technology by which therapeutic effects are achieved by exposing tissues to specific wavelengths of light.The purpose of this review was to gain a better understanding of the science behind non-thermal laser and the evidence supporting its use in dermatology.A group of dermatologists and surgeons recently convened to review the evidence supporting the use of non-thermal laser for body sculpting, improving the appearance of cellulite, and treating onychomycosis.The use of non-thermal laser for body sculpting is supported by three randomized, double-blind, sham-controlled studies (N = 161), one prospective open-label study (N = 54), and two retrospective studies (N = 775). Non-thermal laser application for improving the appearance of cellulite is supported by one randomized, double-blind, sham-controlled study (N = 38). The use of non-thermal laser for the treatment of onychomycosis is supported by an analysis of three non-randomized, open-label studies demonstrating clinical improvement of nails (N = 292).Non-thermal laser is steadily moving into mainstream medical practice, such as dermatology. Although present studies have demonstrated the safety and efficacy of non-thermal laser for body sculpting, cellulite reduction and onychomycosis treatment, studies demonstrating the efficacy of non-thermal laser as a stand-alone procedure are still inadequate.

Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic disorder with prototypical clinical presentations. Its pathophysiology is complex and not fully explained. Recent information regarding the genetic basis of PG and the role of auto-inflammation provides a better understanding of the disease and new therapeutic targets. PG equally affects patients of both sexes and of any age. Uncontrolled cutaneous neutrophilic inflammation is the cornerstone in a genetically predisposed individual. Multimodality management is often required to reduce inflammation, optimize wound healing, and treat underlying disease. A gold standard for the management of PG does not exist and high-level evidence is limited. Multiple factors must be taken into account when deciding on the optimum treatment for individual patients: location, number and size of lesion/ulceration(s), extracutaneous involvement, presence of associated disease, cost, and side effects of treatment, as well as patient comorbidities and preferences. Refractory and rapidly progressive cases require early initiation of systemic therapy. Newer targeted therapies represent a promising pathway for the management of PG, and the main focus of this review is the management and evidence supporting the role of new targeted therapies in PG.

Acute psychological stress (PS) mobilizes metabolic responses that are of immediate benefit to the host, but the current medical paradigm holds that PS exacerbates systemic and cutaneous inflammatory disorders. Although the adverse consequences of PS are usually attributed to neuroimmune mechanisms, PS also stimulates an increase in endogenous glucocorticoids (GCs) that compromises permeability barrier homeostasis, stratum corneum cohesion, wound healing, and epidermal innate immunity in normal skin. Yet, if such PS-induced increases in GC were uniformly harmful, natural selection should have eliminated this component of the stress response. Hence, we hypothesized here instead that stress-induced elevations in endogenous GC could benefit, rather than aggravate, cutaneous function and reduce inflammation in three immunologically diverse mouse models of inflammatory diseases. Indeed, superimposed exogenous (motion-restricted) stress reduced, rather than aggravated inflammation and improved epidermal function in all three models, even normalizing serum IgE levels in the atopic dermatitis model. Elevations in endogenous GC accounted for these apparent benefits, because coadministration of mifepristone prevented stress-induced disease amelioration. Thus, exogenous stress can benefit rather than aggravate cutaneous inflammatory dermatoses through the anti-inflammatory activity of increased endogenous GC.

PURPOSE: The purpose of this learning activity is to provide information about the etiology and treatment of atrophie blanche. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Discuss the pathophysiology of atrophie blanche.2. Explore treatment options for livedoid vasculopathy. ABSTRACT: Atrophie blanche (AB) is a porcelain-white scar that may be seen at the base of a healed ulcer or in association with livedoid vasculopathy (LV). The term AB originally had been used synonymously with LV, whereas LV is a noninflammatory thrombotic condition presenting as either a primary or secondary event (often associated with coagulation).

Approximately 6.5 million Americans suffer from nonhealing wounds. As physicians are increasingly expected to manage chronic wounds, the degree to which formalized wound care education exists as a clinical rotation is unclear. For the first time, the prevalence and characteristics of formal wound electives offered by US medical schools are documented. Online surveys were distributed to 134 US medical schools and to the 74 medical students who completed the wound healing elective at the University of Miami regarding their experiences. School response rate was 41% (n = 55). We found that out of 55 schools, only 7 schools offered a formal wound healing elective. The University of Miami was the only school to include a surgical component. Students' response rate was 39% (n = 29). After completing the elective, 20 students (69%) felt confident in their knowledge of surgical and medical wound management. A majority of students (76%, n = 22) felt that the elective was an important part of the medical school curriculum. In conclusion, we found very few schools offer a formal wound elective and recommend medical schools in formalizing this education through clinical electives. Education should be team-based and multidisciplinary; evidence exists that this is the best approach to managing chronic wounds. Basic tenets of wound care, both medical and surgical, should be emphasized.

Limitation of ankle movement may contribute to calf muscle pump failure, which is thought to contribute to venous leg ulcer formation, which affects nearly 1 million Americans. We therefore wished to study ankle movement in patients with venous leg ulcers and its effect on healing. Using goniometry, we measured baseline ankle range of motion in venous leg ulcer patients from a Phase 2 dose-finding study of an allogeneic living cell bioformulation. Two hundred twenty-seven patients were enrolled in four active treatment groups and one standard-care control group, all receiving compression therapy. Goniometry data from a control group of 49 patients without venous disease, from a previous study, was used for comparison. We found patients with active venous leg ulcers had significantly reduced ankle range of motion compared with the control group (p = 0.001). After 12 weeks of therapy, baseline ankle range of motion was not associated with healing, as there was no significant difference between healed and nonhealed groups, suggesting that ankle range of motion is not important in venous leg ulcer healing or, more likely, is overcome by compression. However, patients with venous ulcers located on the leg (as opposed to the ankle) had significantly higher ankle range of motion for plantar flexion and inversion (p = 0.021 and p = 0.034, respectively) and improved healing with both cell bioformulation and standard care (p = 0.011), suggesting that wound location is an important variable for ankle range of motion as well as for healing outcomes.

Chronic wounds represent a major healthcare burden, costing $25 billion annually, and are associated with high mortality. We previously reported that cutaneous wound healing represented only 0.1% ($29.8 million) of the National Institutes of Health budget. This current study focuses on quantifying the contribution by federal agencies other than the National Institutes of Health for fiscal year 2012. Federal databases including USA Spending, Veterans Affairs, Tracking Accountability in Government Grants Systems, Health Services Research Projects in Progress, and Patient-Centered Outcomes Research Institute, were searched for individual projects addressing wound healing. Twenty-seven projects were identified, totaling funding of $16,588,623 (median: $349,856). Four sponsor institutions accounted for 74% of awarded funds: Department of the Army, National Science Foundation, Department of Veterans Affairs, and Agency for Healthcare Research & Quality. Research projects and cooperative agreements comprised 44% and 37% of awarded grants. New applications and continuing projects represented 52% and 37%. Wound healing represented 0.15% of total medical research funded by the non-National Institutes of Health federal sector. Compared with potential impact on US public health, federal investment in wound research is exiguous. This analysis will draw attention to a disproportionately low investment in wound research and its perils to American public health.

Keratin proteins have been shown to play a key role in wound healing. Controlled keratin gene (KRT) expression promotes cell growth, migration and differentiation, and as an example of the importance of keratin proteins, absence of KRT17 has been shown to delay wound closure. In addition, downregulation of KRT6 and KRT16 in non-healing chronic venous ulcers suggests that deregulation of keratin expression contributes to non-healing phenotype. A sample of 45 chronic wounds of mixed aetiologies presenting in 31 patients were treated with keratin-based novel topical wound healing products. Thirty-seven wounds or 82% of wounds were either healed or reduced in size of >50% during treatment, with 29 (64%) healing completely and an additional 8 wounds experiencing 50% wound size reduction or greater. Of the wounds that responded, 15 required antimicrobial treatment during their course of treatment, suggesting that keratin dressing treatment should be interrupted briefly and then restarted when wound infection occur.

UV radiation is among the most prevalent stressors in humans and diurnal rodents, exerting direct and indirect DNA damage, free-radical production, and interaction with specific chromophores that affects numerous biological processes. In addition to its panoply of effects, UVB (290–320 nm) radiation can specifically affect various local neuroendocrine activities by stimulating the expression of corticotropin-releasing hormone (CRH), urocortin, proopiomelanocortin (POMC), and POMC-derived peptides. Although very little is known about the interplay between the central hypothalamic–pituitary–adrenal (HPA) axis and the skin HPA axis analog, in the current issue Skobowiat and Slominski propose a novel mechanism by which exposure to UVB activates a local HPA axis in skin, which in turn activates the central HPA axis, with the requirement of a functional pituitary gland. This is the first evidence of the local HPA axis in skin contributing to the central neuroendocrine response. This raises intriguing possibilities regarding how local production of cortisol and other HPA axis molecules in skin influence overall systemic levels of cortisol and help regulate local and central HPA axes in the context of homeostasis, skin injury, and inflammatory skin disorders.

Venous leg ulcers are a common complication of venous insufficiency, and result in significant patient morbidity and socioeconomic costs related to care. Patients with venous leg ulcers often fail to achieve complete healing with standard of care treatments even with the addition of the numerous adjuvant therapies available. To gain insight into new treatment directions, we reviewed current clinical trials evaluating the efficacy of novel therapeutics in the treatment of venous ulcers.

A chronic wound fails to complete an orderly and timely reparative process and places patients at increased risk for wound complications that negatively impact quality of life and require greater health care expenditure. The role of extracellular matrix (ECM) is critical in normal and chronic wound repair. Not only is ECM the largest component of the dermal skin layer, but also ECM proteins provide structure and cell signalling that are necessary for successful tissue repair. Chronic wounds are characterised by their inflammatory and proteolytic environment, which degrades the ECM. Human acellular dermal matrices, which provide an ECM scaffold, therefore, are being used to treat chronic wounds. The ideal human acellular dermal wound matrix (HADWM) would support regenerative healing, providing a structure that could be repopulated by the body's cells. Experienced wound care investigators and clinicians discussed the function of ECM, the evidence related to a specific HADWM (Graftjacket(®) regenerative tissue matrix, Wright Medical Technology, Inc., licensed by KCI USA, Inc., San Antonio, TX), and their clinical experience with this scaffold. This article distills these discussions into an evidence-based and practical overview for treating chronic lower extremity wounds with this HADWM.

Langerhans cells (LCs) are a specialized subset of epidermal dendritic cells. They represent one of the first cells of immunologic barrier and play an important role during the inflammatory phase of acute wound healing. Despite considerable progress in our understanding of the immunopathology of diabetes mellitus and its associated comorbidities such as diabetic foot ulcers (DFUs), considerable gaps in our knowledge exist. In this study, we utilized the human ex vivo wound model and confirmed the increased epidermal LCs at wound edges during early phases of wound healing. Next, we aimed to determine differences in quantity of LCs between normal human and diabetic foot skin and to learn if the presence of LCs correlates with the healing outcome in DFUs. We utilized immunofluorescence to detect CD207+ LCs in specimens from normal and diabetic foot skin and DFU wound edges. Specimens from DFUs were collected at the initial visit and 4 weeks later at the time when the healing outcome was determined. DFUs that decreased in size by >50 % were considered to be healing, while DFUs with a size reduction of

Chronic cutaneous wounds are a major burden on patients, healthcare providers, and the US healthcare system. This study, carried out in part by the Wound Healing Society's Government Regulatory Committee, aimed to evaluate the current state of National Institutes of Health funding of cutaneous wound healing-related research projects. National Institutes of Health Research Portfolio Online Reporting Tools Expenditures & Results system was used to identify wound healing projects funded by the National Institutes of Health in the 2012 fiscal year. Research projects focusing on cutaneous wound prevention/education, mechanisms, complications, treatment, or imaging/monitoring were included in the analysis. Ninety-one projects were identified, totaling a collective funding of $29,798,991 and median funding of $308,941. Thirteen institutes/centers from the National Institutes of Health were responsible for awarding funds; three of which (National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases) accounted for 60.4% of the grant funding. The predominant funding mechanisms included R01 (48.3%), R43 (14.3%), and R21 (9.9%). New applications and pre-existing applications accounted for 39.6 and 55.0% of the awarded grants, respectively. Grants awarded to investigators affiliated with universities accounted for 68.1% of grants and 25.3% were to investigators in the private sector. This analysis of current National Institutes of Health funding may facilitate more transparency of National Institutes of Health-allocated research funds and serve as an impetus to procure additional support for the field of wound healing.

Livedoid vasculopathy is a bilateral painful and recurrent cutaneous ulcerative disorder of the legs that leads to atrophie blanche, atrophic white-porcelain scars, and is associated with disorders of fibrinolysis and/or coagulation. We present a young boy with an association between livedoid vasculopathy in the area of a previous involuted cutaneous hemangioma. We found 4 uncommon abnormalities associated with thrombo-occlusive events: heterozygous 20210 A→G genotype of prothrombin, reduced activity of anticoagulation proteins C and S, and elevated lipoprotein (a).

Chronic DFUs are a growing global health concern due to the implied high rates of morbidity and mortality. Standard-of-care modalities sometimes are not sufficient for some recalcitrant ulcers. The use of adjuvant topical therapies including advanced dressings and biologic therapies should be considered in patients whose DFU did not reduce in size after receiving standard care for a period of 4 weeks. These advanced treatments must be used in combination with standard care measures, including debridement, moist wound healing, offloading, and infection control.

Biofilms play an important role in the development and pathogenesis of many chronic infections. Oral biofilms, more commonly known as dental plaque, are a primary cause of oral diseases including caries, gingivitis, and periodontitis. Oral biofilms are commonly studied as model biofilm systems as they are easily accessible; thus, biofilm research in oral diseases is advanced with details of biofilm formation and bacterial interactions being well elucidated. In contrast, wound research has relatively recently directed attention to the role biofilms have in chronic wounds. This review discusses the biofilms in periodontal disease and chronic wounds with comparisons focusing on biofilm detection, biofilm formation, the immune response to biofilms, bacterial interaction, and quorum sensing. Current treatment modalities used by both fields and future therapies are also discussed.

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.

Chronic wounds are an increasingly prevalent disease with a significant healthcare burden. These wounds often do not respond to standard of care therapy alone, requiring the use of adjuvant therapies. Epidermal grafting, previously utilized primarily for correction of leukoderma, is increasingly being recognized as a beneficial therapy for wounds, both acute and chronic. Epidermal grafting has been shown to be effective in the management of chronic wounds, with successful healing in refractory patients. It has not only been shown to be effective, but it is also associated with lower cost and morbidity than traditional skin grafting techniques as well as improved donor site healing. Through the use of a novel epidermal harvesting system, the CelluTome™ Epidermal Harvesting System (KCI, an Acelity company, San Antonio, TX), this treatment modality has become more standardized, reproducible, and easy to use as well as less time consuming, making its use in the clinical setting more convenient and beneficial. Epidermal grafting, therefore, represents a promising, efficacious, and cost-effective option for treatment of refractory non-healing wounds.

A wound can be defined as a disruption in the normal structure and function of the skin and soft tissues. Caused by a variety of different etiologies and mechanisms, wounds are further divided into acute or chronic wounds. A loop may ensue as these wounds may also create stress. For patients with diabetes mellitus, the fear of having a new ulcer generates anxiety and distress. Patients healing from burn wounds often suffer from post-traumatic stress disorder (7 % at discharge and 22 % at follow up). Moreover, stress and pain can result from wound care itself. Dressing changes are often painful for patients, doctor’s appointments and wound care visits can be taxing financially and time consuming, thus inducing anxiety and stress.

This issue provides a clinical overview of venous leg ulcers, focusing on prevention, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.

The present status of clinical leg ulcer healing research was reviewed by 25 experts over 2 days on September 28 and 29, 2015. Multiple clinical effectiveness reviews were presented suggesting that published clinical wound healing research often does not meet present (2015) evidence based standards. Specific areas requiring remediation were highlighted and approaches to overcoming existing challenges were proposed. Participants using anonymous voting technology developed an action plan to resolve perceived deficiencies. Statements were accepted if 75% of participants agreed. Older patients with a high frequency of comorbid conditions posed particular difficulties in designing clinical research protocols and better diagnostic categorization is necessary A standardized model template for collecting information about diagnosis and evaluation of the effect of interventions on healing of all types of leg ulcers was considered a high priority. Such a model template could be modified depending on the specific etiology of the leg ulcers. Generally agreed on quantifiable standards to establish degree of morbidity was considered a high priority. There was universal agreement that sources of funding and conflicts of interest needed to be disclosed in presentations and all publications. All clinical research studies should be registered with appropriate authorities. There was substantial enthusiasm for a clinical research network with quality standards for membership and an advisory research core available to investigators. Such a network should be funded and actively managed to insure long-term viability. The governance of such an entity needs to be established by the wound care community. The present trend to integrate patients into the clinical research process was endorsed and there was enthusiasm to develop patient advocacy for wound healing research.

A man in his 60s with recurrent venous leg ulcers (VLUs) presented with an 18-month history of a VLU on his medial left leg measuring 59.3 cm(2). He had been treated with multi- component compression bandages without significant decrease in ulcer size. Given the ulcer's size, refractory nature, and history of recurrence, the authors sought to optimize the patient's healing.Approximately 23% of the total wound was treated using punch grafts (PGs) harvested from different locations on the body based on hair density using the "stick and place" method.One month later, a 56% reduction in ulcer size was observed, especially in the area that received hair-bearing skin.Punch grafts from hair-bearing skin are a viable source of follicular stem cells and may be superior to PG from nonhair-bearing skin for the treatment of chronic wounds.

Treatment of chronic wounds can present a challenge, with many patients remaining refractory to available advanced therapies. As such, there is a strong need for the development of new products. Unfortunately, despite this demand, few new wound-related drugs have been approved over the past decade. This is in part due to unsuccessful clinical trials and subsequent lack of Food and Drug Administration (FDA) approval. In this article, we discuss the FDA approval process, how it relates to chronic wound trials, common issues that arise, and how best to manage them. Additionally, problems encountered specific to diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are addressed. Careful construction of a clinical trial is necessary in order to achieve the best possible efficacy outcomes and thereby, gain FDA approval. How to design an optimal trial is outlined.

Diseases of elderly adults are becoming increasingly important as life expectancy gradually rises worldwide. To promote healthy aging, it is important to understand the skin changes associated with aging. This review focuses on the special considerations for some of the more common dermatological disorders in elderly adults and examines presentation, contributing factors, and association with systemic diseases.

The rising costs of caring for chronic cutaneous ulcers (CCUs) and recent appreciation of the mortality of CCUs have led to consideration of the reasons for the failure to have new drug therapies. No new chemical entities to heal CCUs have been approved by the Food and Drug Administration (FDA) in over a decade, in part due to an inability to reach the FDA accepted end point of "complete wound closure." The frequent failure to reach the complete closure end point brings forward the question of the relevance of other healing end points such as improved quality of life, or partial healing. Because CCUs carry a prognosis and mortality rate worse than many cancers, it is reasonable to compare the FDA trial end points for cancer drug approval with those for CCUs. And the difference is quite striking. While there is only one end point for CCUs, there are five surrogate and three direct end points for cancers. In contrast to cancer, surrogate end points and partial healing are not acceptable for therapies aimed at CCUs. For example, making tumors smaller is an acceptable end point, but making CCUs smaller is not and improvement in the signs and symptoms of cancer is an acceptable end point for cancers but not CCUs. As CCUs carry a prognosis and mortality rate worse than many cancers, we believe a reconsideration of end points for CCUs is highly warranted.

Since the establishment of the guidelines for the treatment of venous ulcers by the Wound Healing Society in 2006, there has been an abundance of new literature, both in accord and discord with the guidelines. The goal of this update is to highlight new findings since the publication of these guidelines to assist practitioner and patient in appropriate health care decisions, as well as to drive future research endeavors.

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P=0.3 for BCC and P=0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs.

This study was designed to compare the ultraportable mechanically powered Smart Negative Pressure (SNaP) Wound Care System (Spiracur, Sunnyvale, CA) with the electrically powered Vacuum-Assisted Closure (VAC) Therapy System (Kinetic Concepts, Inc. [KCI], San Antonio, TX) in a multicenter, comparative efficacy, noninferiority-powered, randomized controlled trial. We enrolled 132 people with noninfected, nonischemic, nonplantar lower extremity diabetic and venous wounds. Each subject was randomly assigned (1:1) to treatment with either system in conjunction with appropriate off-loading and compression therapy. The trial evaluated treatment for up to 16 weeks or complete wound closure (defined as complete reepithelialization without drainage). Primary end point analysis of wound size reduction found that SNaP-treated subjects demonstrated noninferiority to the VAC-treated subjects at 4, 8, 12, and 16 weeks (p = 0.0030, 0.0130, 0.0051, and 0.0044, respectively). Kaplan-Meier analysis showed no significant difference in complete wound closure between SNaP- and VAC-treated subjects at all time points. Device related adverse events and complications such as infection were also similar between treatment groups. These data support similar wound healing outcomes between the SNaP system and the VAC system in the population studied.

Keratin gene expression is regarded as a hallmark of epidermal biology. It demarcates the three keratinocyte phenotypes: basal (expressing KRT5 and KRT14), differentiating (expressing KRT1 and KRT10), and activated (wound healing), which is characterized by expression of KRT6, KRT16, and KRT17. Activated keratinocytes are among the first signals of epidermal wound healing. In addition, they are found deregulated in nonhealing chronic wounds. To examine keratins as a potential modality for wound-healing disorders, we evaluated two different keratin dressings, liquid or solid, and assessed their effects of epithelialization and closure using porcine partial-thickness wound-healing model in vivo. We found that both forms of keratin dressings accelerated closure and epithelialization, achieving statistically significant differences on day 5. Evidence suggesting early onset of epithelialization was corroborated further by gene expression analyses revealing induction of KRT6A, KRT16, and KRT17 by day 2 postwounding. The data suggest that keratin dressings may stimulate epithelialization by enhancing the activation of keratinocytes. We conclude that keratin-containing dressings can accelerate wound healing and closure. Further studies are needed to determine the molecular mechanisms of this activation.

For example, ionizing radiation, although beneficial for treating cancer, has negative effects on surrounding uninvolved tissues. Fragile and friable areas of damaged skin after radiation may lead to chronic, painful, and recalcitrant ulcers and, at times, bony changes. It may also result in more difficult healing after surgery and recurrence of the wound even with minor trauma. Despite improvements in radiation therapy techniques and equipment, chronic radiation ulcers are often resistant to conventional treatment modalities or advanced surgical options such as flap coverage or skin grafting and continue to be a therapeutic challenge. We present a case of a radiation ulcer treated using tissue engineered skin, discuss the pathophysiology of radiation-induced skin damage, and review the current management strategies.

Background: Skin cancer is frequently suspected by nondermatologists. Many dermatology practices currently do not triage referrals from nondermatologists. Little is known how nondermatologists describe lesions of concern when making referrals. Objective: We sought to assess the descriptive terminology used by nondermatologists when referring patients with potential cutaneous malignancies. Methods: We completed a retrospective chart review of 400 patients referred by nondermatologists for skin lesions suspicious of malignancy. We collected the reason for the consult, all terminology used to characterize the lesion, and the final diagnosis. Results: Clinicians documented 680 reasons for referring patients with suspicious lesions. General concern (rule out malignancy) without specific descriptors was used in 78 referrals, of which 23% (n = 18) were found to be associated with malignancy. Specific descriptive terminologies used most frequently by nondermatologists to describe suspicious lesions were: hyperpigmented (n = 71), changing size (n = 69), nonhealing (n = 55), irregular border (n = 52), irritated and/or scaly (n = 40), and raised (n = 33). A statistically significant correlation (P < 0.05) was found between skin cancer and the following terms: nonhealing, ulcerated, and rule out basal cell carcinoma. Conclusion: The descriptive terminology of potential cutaneous malignancies utilized by nondermatologists may provide important clues to aid dermatologists in triage decisions. Specifically, ulcerated, nonhealing, and rule out basal cell carcinoma may be terms that indicate the patient should be seen by the dermatologist in a timely manner.

Psoriasis afflicts 2-3% of the world's population. Affected patients commonly have risk factors for cardiovascular disease (CVD). In addition, psoriasis is independently associated with CVD and mortality.To determine which CVD risk factors are associated with psoriasis independent of confounders, whether psoriasis is associated with CVD independent of CVD risk factors, and whether there is increased mortality among patients with psoriasis.MEDLINE, Embase, and Cochrane Collaborations from inception through October 2009. We reviewed bibliographies of retrieved articles for additional references.Cross-sectional, cohort-based, case-control, and randomized controlled trials which involved patients with psoriasis.Two investigators independently reviewed studies and resolved any discrepancies by consensus.Of the 2,303 articles identified by literature search, 90 studies met inclusion criteria for this review; 15 were cohort-based studies, 45 were case-control, and 30 were cross-sectional.The quality of evidence was limited by study heterogeneity and lack of large scale prospective studies with long-term follow-up.Patients with psoriasis demonstrate a higher prevalence of cardiovascular risk factors and appear to be at increased risk for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. This increase in vascular disease may be independent of shared risk factors and may contribute to the increase in all-cause mortality. Future research should aim to more confidently distinguish between a true causal relationship or merely an association resulting from multiple shared risk factors. Physicians should screen for and aggressively treat modifiable risk factors for CVD in patients with psoriasis.

We assessed the safety and efficacy of Formulated Collagen Gel (FCG) alone and with Ad5PDGF-B (GAM501) compared with Standard of Care (SOC) in patients with 1.5-10.0 cm(2) chronic diabetic neuropathic foot ulcers that healed

The purpose of this study was to compare the ultraportable mechanically powered Smart Negative Pressure (SNaP(®)) Wound Care System to the traditional electrically powered Vacuum-Assisted Closure (VAC(®)) Therapy System in the treatment of chronic lower extremity wounds. This 12-center randomized-controlled trial of patients with noninfected, nonischemic, nonplantar lower extremity wounds had enrolled 65 patients, as of January 5, 2010, at the time of a planned interim analysis. Subjects were randomly assigned to treatment with either the SNaP(®) or VAC(®) Systems. The trial evaluated treatment for up to 16 weeks or till complete closure was achieved. Fifty-three patients (N=27 SNaP(®), N=26 VAC(®)) completed at least 4 weeks of therapy. Thirty-three patients (N=18 SNaP(®), N=15 VAC(®)) completed the study with either healing or 16 weeks of therapy. At the time of planned interim analysis, no significant differences (p=0.99) in the proportion of subjects healed between the two devices evaluated were found. In addition, the percent wound size reduction between treatment groups was not significantly different at 4, 8, 12, and 16 weeks, with noninferiority analysis at 4 weeks of treatment reaching the p-value

Here, we define dynamic reciprocity (DR) as an ongoing, bidirectional interaction among cells and their surrounding microenvironment. In this review, we posit that DR is especially meaningful during wound healing as the DR-driven biochemical, biophysical, and cellular responses to injury play pivotal roles in regulating tissue regenerative responses. Such cell-extracellular matrix interactions not only guide and regulate cellular morphology, but also cellular differentiation, migration, proliferation, and survival during tissue development, including, e.g., embryogenesis, angiogenesis, as well as during pathologic processes including cancer, diabetes, hypertension, and chronic wound healing. Herein, we examine DR within the wound microenvironment while considering specific examples across acute and chronic wound healing. This review also considers how a number of hypotheses that attempt to explain chronic wound pathophysiology may be understood within the DR framework. The implications of applying the principles of DR to optimize wound care practice and future development of innovative wound healing therapeutics are also briefly considered.

IntroductionChronic venous insufficiency (CVI) affects up to one-third of the adult population yet venous leg ulcers (VLU), a significant complication of CVI, only affect 1%–2% of adults in the USA. Why some develop VLU and others do not is unclear. VLU have a significant impact on quality of life and are extremely costly and difficult to treat. Moreover, VLU prevalence is increasing, doubling in the last 20 years. In order to characterise the differences between people with CVI and those who ultimately develop VLU, we aim to set up the unique venous insufficiency in South Florida cohort.Methods and analysisSubjects will be recruited from the University of Miami Hospital and Clinic’s vascular laboratory database, which began in July 2011. Any adult age 18–95 who has had venous reflux detected on duplex ultrasound of the lower extremities is included. Approximately 2500 patients are already in the database that meet these criteria, with an estimated 2500 additional potential subjects to be recruited from the vascular laboratory database over the next 5 years. Subjects with a history of VLU prior to the duplex study date will be excluded. Data will be collected via review of the Doppler study report, patient phone interview and review of the electronic medical record. Subjects will be contacted for follow-up every 3 months for at least 5 years until the study endpoint, development of first VLU (fVLU), is reached. In order to estimate the time from reflux documentation to fVLU, Kaplan-Meier survival curves will be constructed. Cox proportional hazard regression models will be constructed to investigate possible risk factors.Ethics and disseminationThis study is approved by the University of Miami’s Institutional Review Board. We hope to present the results of this study to the scientific community at conferences and in peer-reviewed journals.

Statins, HMG-CoA reductase inhibitors, are common cholesterol-lowering drugs. Recent studies suggest that statins may have potential as novel treatments for diverse conditions, ranging from sepsis and inflammatory diseases to chronic wounds and bone fractures. The diverse pleiotropic actions of statins are probably related to reduced isoprenylation of downstream targets of the mevalonate pathway and their binding to several nuclear hormone receptors. Statins exert their anti-inflammatory effect by inhibiting the release of C-reactive peptide, chemokines, cytokines and adhesion molecules, which may make them a powerful addition to the dermatologic anti-inflammatory medication arsenal. Along with reducing inflammation, statins have the potential to heal chronic wounds by decreasing farnesyl pyrophosphate, facilitating vascular relaxation, promoting neovascularization and reducing bacterial load. A review of the literature elucidates that route of administration, dose and type of statin appear to impact the ...