Pharmacological and Genetic Inhibition of Caveolin-1 Promotes Epithelialization and Wound Closure.

Chronic wounds-including diabetic foot ulcers, venous leg ulcers, and pressure ulcers-represent a major health problem that demands an urgent solution and new therapies. Despite major burden to patients, health care professionals, and health care systems worldwide, there are no efficacious therapies approved for treatment of chronic wounds. One of the major obstacles in achieving wound closure in patients is the lack of epithelial migration. Here, we used multiple pre-clinical wound models to show that Caveolin-1 (Cav1) impedes healing and that targeting Cav1 accelerates wound closure. We found that Cav1 expression is significantly upregulated in wound edge biopsies of patients with non-healing wounds, confirming its healing-inhibitory role. Conversely, Cav1 was absent from the migrating epithelium and is downregulated in acutely healing wounds. Specifically, Cav1 interacted with membranous glucocorticoid receptor (mbGR) and epidermal growth factor receptor (EGFR) in a glucocorticoid-dependent manner to inhibit cutaneous healing. However, pharmacological disruption of caveolae by MßCD or CRISPR/Cas9-mediated Cav1 knockdown resulted in disruption of Cav1-mbGR and Cav1-EGFR complexes and promoted epithelialization and wound healing. Our data reveal a novel mechanism of inhibition of epithelialization and wound closure, providing a rationale for pharmacological targeting of Cav1 as potential therapy for patients with non-healing chronic wounds.

A Framework to Assist Providers in the Management of Patients with Chronic, Nonhealing Wounds.

GENERAL PURPOSE: To describe the development of an evidence-based wound electronic medical record (WEMR) framework for providers to execute timely, protocol-based, best-practice care for patients with chronic, nonhealing wounds. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After completing this continuing education activity, you should be better able to: ABSTRACT: The care of patients with nonhealing wounds involves a host of treatment modalities. The authors developed a wound-specific framework to enhance provider management of these wounds and a summary sheet to involve patients and caregivers in their own healthcare to improve treatment adherence and outcomes. Implementing evidence-based practice for chronic wounds enables corrective actions to optimize care.

Practical Application of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Patients with Wounds.

Rapidly evolving advances in wound-care technologies and treatment modalities, including locally injectable granulocyte-macrophage colony-stimulating factor (GM-CSF), are increasingly being used. Based on its role in the stimulation and recruitment of key contributors to wound healing, such as keratinocytes, macrophages, and fibroblasts, GM-CSF is considered to play an essential role in the wound-healing cascade. Synthetic GM-CSF has been shown to have a positive effect on the healing of chronic wounds when given as a local injection in a small number of patients. Subsequent randomized, controlled trials demonstrated that GM-CSF accelerated the healing of chronic wounds. This paper reviews the proposed mechanism of action of GM-CSF in wound healing. We also describe its method of application in the operating room at a tertiary care center for patients with wounds. Key Messages: Many types of chronic wounds have an altered keratinocyte and macrophage function that can be potentially assuaged by the addition of locally injected growth factor therapy to standard-of-care treatment. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be beneficial for the treatment of chronic, non-healing wounds. This article reviews the data on GM-CSF, reports a proposed mechanism of action, and describes its use by a team of wound surgeons.

A Perioperative Approach to Increase Limb Salvage When Treating Foot Ulcers in Patients With Diabetes.

Foot ulceration in patients with diabetes increases the risk of lower extremity amputation. Major amputations produce substantial adverse consequences, increase length of hospital stay, diminish quality of life, and increase mortality. In this article, we describe approaches that decrease amputations and improve the quality of life for patients with diabetes and foot ulcers. We highlight the role of the perioperative nurse, who is essential to providing optimal patient care in the perioperative period. Perioperative care of patients with diabetes involves providing optimal surveillance for a break in the skin of the foot, screening for neuropathy, following guidelines for foot ulcer infections, preparing for pathophysiology-based debridement, using adjuvant therapies, and offloading the patient's affected foot. Nurses should understand the disease process and pathophysiology and how to use these approaches in the perioperative setting to assist in curtailing the morbidity and mortality associated with foot ulcers in patients with diabetes.

Protocol for Psychopharmacologic Management of Behavioral Health Comorbidity in Adult Patients with Diabetes and Soft Tissue Infections in a Tertiary Care Hospital Setting.

GENERAL PURPOSE: To provide information about the effect of psychiatric comorbidities on wound healing in patients with diabetes mellitus (DM). TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Discuss the connection between DM and the development of psychiatric comorbidities.2. Identify the drugs recommended in the treatment of these psychiatric comorbidities.3. List cautions and contraindications related to the drugs discussed. ABSTRACT: In patients with diabetes mellitus type 2, psychiatric comorbidities such as depressive and anxiety disorders are 60% or more prevalent than in the general population. The severity of mental illness and the duration of diabetes have been shown to correlate with worsening glycemic control, thus impeding wound healing. A retrospective chart review was conducted in all patients with diabetes mellitus admitted to the wound service with prior or current psychiatric symptoms of anxiety, depression, or cognitive impairment. A psychopharmacologic protocol was developed based on the clinical data collected and treatment parameters used by the behavioral health consultation liaison service.

Modalities to Treat Venous Ulcers: Compression, Surgery, and Bioengineered Tissue.

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.

Major Histopathologic Diagnoses of Chronic Wounds.

PURPOSE: To clarify the histopathology of acute osteomyelitis, chronic osteomyelitis, primary vasculitis, and secondary-type vasculitis. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Describe the parameters and significance of this study.2. Identify chronic wound diagnosis and treatment.3. Differentiate the histopathology of osteomyelitis and vasculitis. OBJECTIVE: The presence of a chronic wound can result in significant morbidity/mortality. Understanding the pathological alterations of wound tissue that are refractory to standard wound therapy is essential for effective wound management and healing. The authors describe 4 wound etiologies, specifically, acute osteomyelitis, chronic osteomyelitis, primary vasculitis, and secondary-type vasculitis. SETTING: A tertiary care hospital. DESIGN: A retrospective review of 1392 wound operations performed during a 24-month period at a tertiary care hospital was conducted. Tissue specimens reviewed included soft tissue infections of the lower extremity, sacrum, hip/pelvis, trunk, perineum, and buttocks. MAIN RESULTS: Acute osteomyelitis is defined as bone tissue with a predominance of polymorphonuclear leukocytes, evidence of osteoclast bone resorption with scalloping of the cortical bone edges, and bone detritus. Chronic osteomyelitis is defined as bone tissue with a significant amount of fibrosis surrounding devitalized tissue and heavy infiltration of lymphocytes and plasma cells. Primary-type vasculitis is defined primarily as inflammation and necrosis of blood vessel walls. In cutaneous lesions of granulomatosis with polyangiitis, ulceration with numerous inflammatory granulomas is seen in the papillary dermis. Secondary vasculitis is defined by vessel wall infiltration by inflammatory cells and fibrinoid necrosis of the small vessel wall. CONCLUSIONS: Pathologies of these 4 types of wounds can complicate standard algorithms designed for diagnosis and treatment, and accurate diagnosis through histopathologic analysis can help tailor targeted treatment.

Chronic wound repair and healing in older adults: current status and future research.

Older adults are more likely to have chronic wounds than younger people, and the effect of chronic wounds on quality of life is particularly profound in this population. Wound healing slows with age, but 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 effect of age and accompanying multimorbidity 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 article, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify research questions to guide future study of age-associated changes in chronic wound healing.

Chronic wound repair and healing in older adults: current status and future research.

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.

Perioperative use of bispectral (BIS) monitor for a pressure ulcer patient with locked-in syndrome (LIS).

The bispectral (BIS) monitor uses brain electroencephalographic data to measure the depth of sedation and pharmacological response during anaesthetic procedures. In this case, the BIS monitor was used for another purpose, to demonstrate postoperatively to the nursing staff that a patient with history of locked-in syndrome (LIS), who underwent pressure ulcer debridement, had periods of wakefulness and apparent sensation, even with his eyes closed. Furthermore, as patients with LIS can feel pain, despite being unable to move, local block or general anaesthesia should be provided for sharp surgical debridement and other painful procedures. This use of the BIS has shown that as a general rule, the staff should treat the patient as though he might be awake and sensate even if he does not open his eyes or move his limbs. The goal of this study was to continuously monitor pain level and communicate these findings to the entire wound team, i.e. anaesthesiologists, surgeons and nurses.

Wounds in patients with HIV.

Highly active antiretroviral therapy has dramatically reduced morbidity and mortality among patients who are HIV-positive. A retrospective review of the authors' data separated subjects into cohorts based on HIV status and matched them for age and gender. The authors' data reveal a higher fraction of venous ulcers compared with a lower fraction of pressure ulcers in the seropositive population.

Clinical application of growth factors and cytokines in wound healing.

Wound healing is a complex and dynamic biological process that involves the coordinated efforts of multiple cell types and is executed and regulated by numerous growth factors and cytokines. There has been a drive in the past two decades to study the therapeutic effects of various growth factors in the clinical management of nonhealing wounds (e.g., pressure ulcers, chronic venous ulcers, diabetic foot ulcers). For this review, we conducted an online search of Medline/PubMed and critically analyzed the literature regarding the role of growth factors and cytokines in the management of these wounds. We focused on currently approved therapies, emerging therapies, and future research possibilities. In this review, we discuss four growth factors and cytokines currently being used on and off label for the healing of wounds. These include granulocyte-macrophage colony-stimulating factor, platelet-derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor. While the clinical results of using growth factors and cytokines are encouraging, many studies involved a small sample size and are disparate in measured endpoints. Therefore, further research is required to provide definitive evidence of efficacy.

Acute lung injury following the use of granulocyte-macrophage colony-stimulating factor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor with immunostimulatory effects that include the activation and priming of neutrophils. Neutrophils are an important part of the human immune system, yet they have been implicated in the pathogenesis of acute lung injury (ALI). GM-CSF has been found to increase the amount of activated neutrophils recruited to the lung tissue as well as to increase the life span of neutrophils leading to substantial lung tissue injury and the development of ALI. While, there have been few cases reported of ALI following GM-CSF, the experience reported here is the first of ALI subsequent to local administration of GM-CSF in a patient with significant pulmonary comorbidities.

Induction of specific microRNAs inhibits cutaneous wound healing.

Chronic nonhealing wounds, such as venous ulcers (VUs), are a widespread and serious medical problem with high morbidity and mortality. The molecular pathology of VUs remains poorly understood, impeding the development of effective treatment strategies. Using mRNA expression profiling of VUs biopsies and computational analysis, we identified a candidate set of microRNAs with lowered target gene expression. Among these candidates, miR-16, -20a, -21, -106a -130a, and -203 were confirmed to be aberrantly overexpressed in a cohort study of 10 VU patients by quantitative PCR and in situ hybridizations. These microRNAs were predicted to target multiple genes important for wound healing, including early growth response factor 3, vinculin, and leptin receptor (LepR). Overexpression of the top up-regulated miRNAs, miR-21 and miR-130a, in primary human keratinocytes down-regulated expression of the endogenous LepR and early growth response factor 3. The luciferase reporter assay verified LepR as a direct target for miR-21 and miR-130a. Both miR-21 and miR-130a delayed epithelialization in an acute human skin wound model. Furthermore, in vivo overexpression of miR-21 inhibited epithelialization and granulation tissue formation in a rat wound model. Our results identify a novel mechanism in which overexpression of specific set of microRNAs inhibits wound healing, resulting in new potential molecular markers and targets for therapeutic intervention.

Regional anaesthesia with sedation protocol to safely debride sacral pressure ulcers.

A treatment challenge for patients with sacral pressure ulcers is balancing the need for adequate surgical debridement with appropriate anaesthesia management. We are functioning under the hypothesis that regional anaesthesia has advantages over general anaesthesia. We describe our regional anaesthesia protocol for perioperative and postoperative management.

Anesthesia protocol for heel pressure ulcer debridement.

Heel ulcers are clinically challenging. Limited subcutaneous tissue covering the calcaneus bone makes the heel vulnerable to pressure injury. Adequate debridement of fibrotic, infected, and necrotic tissue is essential for healing. The authors report a standardized anesthesia protocol using regional anesthesia with sedation rather than general anesthesia for heel debridement.

Mesenchymal stem cell therapy and delivery systems in nonhealing wounds.

OBJECTIVE: The objective of the study was to inform wound care practitioners of mesenchymal stem cell application for nonhealing wounds. Recent advances in delivery systems are also discussed in order to highlight potential improvements toward clinical application of stem cell therapy for chronic wounds. DATA SOURCES: MEDLINE and PubMed Central were searched for scientific studies regarding the use of mesenchymal stem cells and delivery systems in wound healing. STUDY SELECTION: Preclinical studies using stem cells as therapeutic modality for chronic wounds were selected for this review. DATA EXTRACTION: Information on study design, sample size and characteristics, stem cell source, type of delivery systems, and rate and time of wound closure was abstracted. DATA SYNTHESIS: Application of mesenchymal stem cells improved wound healing in experimental and clinical settings. Advances in stem cell therapy and delivery vehicles offer promising alternatives to current limited therapeutic modalities for chronic wounds. CONCLUSIONS: Stem cell therapy has recently emerged as a promising therapeutic strategy for nonhealing wounds. Further research is needed to evaluate the relationship between the various delivery systems and stem cells in order to maximize their therapeutic effects. Development of novel delivery vehicles for stem cells can open new opportunities for more effective cell therapy of chronic wounds.

Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.

Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 ß-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11ß-hydroxysteroid dehydrogenase 2 (11ßHSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1ß, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1ß production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.

Micro-RNAs: New Regulators of Wound Healing.

Chronic wounds represent a significant burden to patients, health care professionals, and the health care system. Micro-RNAs (miRNAs) have recently emerged as a novel class of gene expression modulators involved in regulation of multiple biological processes, including development, differentiation, organogenesis, inflammation, cell proliferation, growth control, and apoptosis. Importantly, aberrant expression or activity of miRNAs can lead to a disease state. However, the role of miRNAs in chronic wounds remains to be elucidated. This article reviews available literature on the role of miRNAs in a range of processes important for successful wound healing including epidermal differentiation and proliferation, inflammation and angiogenesis. The potential role of miRNAs in normal wound healing and their contribution to chronic wound pathology has been anticipated. The prospective use of miRNAs as markers for surgical debridement, and as novel diagnostic and therapeutic targets for chronic wounds is also discussed.