Compression therapy in peripheral artery disease: a literature review.

OBJECTIVE: Our objective is to examine the pathophysiology of oedema in the ischaemic and post-revascularised limb, compare compression stockings to pneumatic compression devices, and summarise compression regimens in patients with severe peripheral artery disease (PAD) without revascularisation, after revascularisation, and in mixed arterial and venous disease. METHOD: A scoping literature review of the aforementioned topics was carried out using PubMed. RESULTS: Compression therapy has been shown to increase blood flow and aid in wound healing through a variety of mechanisms. Several studies suggest that intermittent pneumatic compression (IPC) devices can be used to treat critical limb ischaemia in patients without surgical options. Additionally, compression stockings may have a role in preventing oedema after peripheral artery bypass surgery, thereby diminishing pain and reducing the risk of surgical wound dehiscence. CONCLUSION: Oedema may occur in the ischaemic limb after revascularisation surgery, as well as in combination with venous disease. Clinicians should not fear using compression therapy in PAD.

Oxidant Signaling Mediated by Nox2 in Neutrophils Promotes Regenerative Myelopoiesis and Tissue Recovery following Ischemic Damage.

Ischemic tissue damage activates hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM)-generating myeloid cells, and persistent HSPC activity may drive chronic inflammation and impair tissue recovery. Although increased reactive oxygen species in the BM regulate HSPC functions, their roles in myelopoiesis of activated HSPCs and subsequent tissue recovery during ischemic damage are not well understood. In this paper, we report that deletion of Nox2 NADPH oxidase in mice results in persistent elevations in BM HSPC activity and levels of inflammatory monocytes/macrophages in BM and ischemic tissue in a model of hindlimb ischemia. Ischemic tissue damage induces oxidants in BM such as elevations of hydrogen peroxide and oxidized phospholipids, which activate redox-sensitive Lyn kinase in a Nox2-dependent manner. Moreover, during tissue recovery after ischemic injury, this Nox2-ROS-Lyn kinase axis is induced by Nox2 in neutrophils that home to the BM, which inhibits HSPC activity and inflammatory monocyte generation and promotes tissue regeneration after ischemic damage. Thus, oxidant signaling in the BM mediated by Nox2 in neutrophils regulates myelopoiesis of HSPCs to promote regeneration of damaged tissue.

Use of a National Electronic Health Record Network to Describe Characteristics and Healing Patterns of Sickle Cell Ulcers.

Objective: Sickle cell ulcers affect as many as 15% of patients with sickle cell disease in the United States and severely impact quality of life. An understanding of baseline healing patterns is important to inform study design for future trials that test therapies for this disease. Approach: In this study, an electronic wound management system was leveraged to analyze retrospective data on 133 unique sickle cell patients who were treated across 114 wound healing centers, and to describe their characteristics and healing patterns as compared with those of venous ulcer patients. The data included 198 care episodes for 427 wounds. Results: Patients with sickle cell ulcers were younger and had fewer comorbid diseases than those with venous ulcers. Larger size and longer duration were predictors of poor healing. Between the first and fourth assessments, mean change in area for sickle cell ulcers showed a 58% increase, compared with a 13% decrease for venous ulcers. Kaplan-Meier curves showed poorer healing in sickle cell ulcers than in venous ulcers across all categories of size and duration. Patients with sickle cell ulcers had longer care episodes and were more likely to re-present for care. Innovation: This study reports on the largest data set of sickle cell ulcer patients analyzed to date in the published literature to provide a more detailed understanding of wound healing patterns of this disease. Conclusion: A national network of electronic health records can effectively identify a large number of patients with sickle cell ulcers to support analysis of epidemiology, healing patterns, and health care utilization.

Impact of Hyperbaric Oxygen on More Advanced Wagner Grades 3 and 4 Diabetic Foot Ulcers: Matching Therapy to Specific Wound Conditions.

Objective: The goal of this research was to identify a population of diabetic foot ulcer patients who demonstrate a significant response to hyperbaric oxygen therapy (HBOT) using a large sample size to provide guidance for clinicians when treating these complicated patients. Approach: The effect of HBOT on diabetic foot ulcers, Wagner grades 3 and 4, was evaluated using a retrospective observational real-world data set. The study reported on the overall healing rate, (74.2%) at the population level, for >2 million wounds. Results: When a subgroup of patients of only foot ulcers with a Wagner grade 3 or 4 were considered, the healing rate was only 56.04%. The use of HBOT, without filtering for the number of treatments received, improved the healing rate to 60.01% overall. Healing rates for this same subgroup, however, were improved to 75.24% for patients who completed the prescribed number of hyperbaric treatments. Innovation: This observational study discusses the importance of reporting at the population level, specific wound etiology level, a risk-stratified level, and to then overlay the effect of treatment adherence on those outcomes to provide clinicians with a comprehensive understanding of when to prescribe an advanced modality such as hyperbaric oxygen. Conclusion: The authors provide healing outcomes data from several prior HBOT studies as well as other advanced modalities that have been used in diabetic foot ulcer care for comparison and context.

Baseline factors affecting closure of venous leg ulcers.

OBJECTIVE: The objective of this study was to characterize factors associated with closure of venous leg ulcers (VLUs) in a pooled analysis of subjects from three randomized clinical trials. METHODS: Closure of VLUs after treatment with HP802-247, an allogeneic living cell therapy consisting of growth-arrested human keratinocytes and fibroblasts, vs standard therapy with compression bandaging was evaluated in three phase 3 clinical trials of similar design. Two trials enrolled subjects with VLUs ranging from 2 cm2 to 12 cm2 in area with 12-week treatment periods; the third trial enrolled subjects with VLUs between >12 cm2 and ≤36 cm2 with a 16-week treatment period. The first trial went to completion but failed to demonstrate a benefit to therapy with HP802-247 compared with placebo, and because of this, the remaining trials were terminated before completion. On the basis of no differences in outcomes between groups, subjects from both HP802-247 and control groups were pooled across all three studies. Cox proportional hazards regression analysis was employed to evaluate factors associated with VLU closure. RESULTS: This analysis included data from 716 subjects with VLU. Factors evaluated for association with healing included age, gender, race, diabetes, glycated hemoglobin level, body mass index, treatment (HP802-247 vs compression alone), and ulcer characteristics including location and area and duration at baseline. In an initial model including all of these putative factors, the following were significant at the P < .10 level: diagnosis of diabetes mellitus, gender, wound location (ankle or leg), baseline wound area, and wound duration at baseline. In a final model including only these factors, all but diabetes mellitus were significant at the P < .05 level. Effect sizes were as follows (hazard ratio [95% confidence interval]): female gender (1.384 [1.134-1.690]), wound location on the leg (1.490 [1.187-1.871]), smaller wound area at baseline (0.907 [0.887-0.927]), and shorter wound duration at baseline (0.971 [0.955-0.987]). CONCLUSIONS: Factors associated with VLU lesions including location, area, and duration were important predictors of healing. Women were more likely than men to achieve wound closure. Factors including body mass index, the presence of diabetes mellitus, and higher concentrations of glycated hemoglobin were not significant independent predictors of wound closure in this analysis.

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.

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.

Advanced Technologies to Improve Wound Healing: Electrical Stimulation, Vibration Therapy, and Ultrasound-What Is the Evidence?

BACKGROUND: Cellular energy is required for the healing cascade to occur. A combination of cells, cytokines, chemokines, tissue perfusion, an extracellular matrix, and local forces are also required to allow for human tissue repair to proceed. Although there are many examples of treatment options, energy-based therapies are the least understood, appreciated, and employed by practicing wound care physicians. The recent growth of tissue engineering has encouraged researchers to employ both electrical stimulation and therapeutic ultrasound (US) to stimulate cells, induce migration, and modify tissue constructs. METHODS: The authors have reviewed the literature on electrical stimulation, US, and vibrational therapy and are providing an update to a prior 2007 publication on this topic. The hope was to provide a broad exposure to these treatments but not to create a comprehensive review. A table of evidence was generated from the recent literature to help guide treatment decisions for the clinician. RESULTS: In the current literature, there is much debate over which treatment modality, dosage levels, and timing are optimal. There are numerous in-vitro-based publications that describe mechanism of action and several clinical articles that describe effectiveness of electrical stimulation and US, but few well-controlled and/or randomized trials. The absence of level one evidence has hindered the adoption of these techniques throughout the years. Three energy-based treatment options, electrical stimulation, vibration, and US, will be reviewed along with possible clinical applications CONCLUSIONS: : Although most trials are underpowered with inconsistent treatment settings, physical therapy modality use is increasing in the clinical community. Recent guidelines reference the use of these treatments with increasing evidence level recommendations. At the present time, electrical stimulation carries the greatest level of evidence for clinical use.

Diabetes medications: Impact on inflammation and wound healing.

Chronic wounds are a common complication in patients with diabetes that often lead to amputation. These non-healing wounds are described as being stuck in a persistent inflammatory state characterized by accumulation of pro-inflammatory macrophages, cytokines and proteases. Some medications approved for management of type 2 diabetes have demonstrated anti-inflammatory properties independent of their marketed insulinotropic effects and thus have underappreciated potential to promote wound healing. In this review, the potential for insulin, metformin, specific sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors to promote healing is evaluated by reviewing human and animal studies on inflammation and wound healing. The available evidence indicates that diabetic medications have potential to prevent wounds from becoming arrested in the inflammatory stage of healing and to promote wound healing by downregulating pro-inflammatory cytokines, upregulating growth factors, lowering matrix metalloproteinases, stimulating angiogenesis, and increasing epithelization. However, no clinical recommendations currently exist on the potential for specific diabetic medications to impact healing of chronic wounds. Thus, we encourage further research that may guide physicians on providing personalized diabetes treatments that achieve glycemic goals while promoting healing in patients with chronic wounds.

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.

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.

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-1ß 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.

Calcinosis cutis presenting in the context of long-term therapy for chronic myeloid leukemia: a case report and review of the literature.

Calcinosis cutis is a poorly understood process in which calcium salts deposit in the skin and subcutaneous tissues. Due to its multifactorial pathogenesis, several subtypes and potential etiologies have been described. Presented here is a case of bilateral pretibial calcinosis cutis in a patient on long-term tyrosine kinase inhibitor therapy for chronic myeloid leukemia. The patient initially presented with a right tibial ulceration treated with multiple surgical debridements, antibiotics, and negative pressure wound therapy. The wound was ultimately closed with a split-thickness skin graft. Relevant literature is examined and several possible mechanisms are discussed.

What Do Patients Want? Patient Preference in Wound Care.

Patient preferences are statements made or actions taken by consumers that reflect their desirability of a range of health options. The concept occupies an increasingly prominent place at the center of healthcare reform, and is connected to all aspects of healthcare, including discovery, research, delivery, outcome, and payment. Patient preference research has focused on shared decisions, decisional aids, and clinical practice guideline development, with limited study in acute and chronic wound care populations. The wound care community has focused primarily on patient focused symptoms and quality of life measurement. With increasing recognition of wound care as a medical specialty and as a public health concern that consumes extensive resources, attention to the preferences of end-users with wounds is necessary. This article will provide an overview of related patient-centered concepts and begin to establish a framework for consideration of patient preference in wound care.

Low-intensity vibration improves angiogenesis and wound healing in diabetic mice.

Chronic wounds represent a significant health problem, especially in diabetic patients. In the current study, we investigated a novel therapeutic approach to wound healing--whole body low-intensity vibration (LIV). LIV is anabolic for bone, by stimulating the release of growth factors, and modulating stem cell proliferation and differentiation. We hypothesized that LIV improves the delayed wound healing in diabetic mice by promoting a pro-healing wound environment. Diabetic db/db mice received excisional cutaneous wounds and were subjected to LIV (0.4 g at 45 Hz) for 30 min/d or a non-vibrated sham treatment (controls). Wound tissue was collected at 7 and 15 d post-wounding and wound healing, angiogenesis, growth factor levels and wound cell phenotypes were assessed. LIV increased angiogenesis and granulation tissue formation at day 7, and accelerated wound closure and re-epithelialization over days 7 and 15. LIV also reduced neutrophil accumulation and increased macrophage accumulation. In addition, LIV increased expression of pro-healing growth factors and chemokines (insulin-like growth factor-1, vascular endothelial growth factor and monocyte chemotactic protein-1) in wounds. Despite no evidence of a change in the phenotype of CD11b+ macrophages in wounds, LIV resulted in trends towards a less inflammatory phenotype in the CD11b- cells. Our findings indicate that LIV may exert beneficial effects on wound healing by enhancing angiogenesis and granulation tissue formation, and these changes are associated with increases in pro-angiogenic growth factors.

Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice.

The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of these wounds are sufficient to activate the inflammasome, as wound-conditioned medium activates caspase-1 and induces release of interleukin (IL)-1ß and IL-18 in cultured Mp via a reactive oxygen species-mediated pathway. Importantly, inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds, induced a switch from proinflammatory to healing-associated Mp phenotypes, and increased levels of prohealing growth factors. Furthermore, data generated from bone marrow-transfer experiments from NLRP-3 or caspase-1 knockout to db/db mice indicated that blocking inflammasome activity in bone marrow cells is sufficient to improve healing. Our findings indicate that sustained inflammasome activity in wound Mp contributes to impaired early healing responses of diabetic wounds and that the inflammasome may represent a new therapeutic target for improving healing in diabetic individuals.

Skin blood flow response to locally applied mechanical and thermal stresses in the diabetic foot.

Diabetic foot ulcers are one of the most common complications in diabetics, causing significant disabilities and decreasing the quality of life. Impaired microvascular reactivity contributes to the development of diabetic foot ulcers. However, underlying physiological mechanisms responsible for the impaired microvascular reactivity in response to extrinsic causative factors of foot ulcers such as mechanical and thermal stresses have not been well investigated. A total of 26 participants were recruited into this study, including 18 type 2 diabetics with peripheral neuropathy and 8 healthy controls. Laser Doppler flowmetry was used to measure skin blood flow at the first metatarsal head in response to a mechanical stress at 300mmHg and a fast thermal stress at 42°C. Wavelet analysis of skin blood flow oscillations was used to assess metabolic, neurogenic and myogenic controls. Our results indicated that diabetics have significantly decreased metabolic, neurogenic and myogenic responses to thermal stress, especially in the neurogenic and myogenic controls during the first vasodilatory response and in the metabolic control during the second vasodilatory response. Diabetics have a significantly decreased myogenic response to mechanical stress during reactive hyperemia. Our findings demonstrate that locally applied mechanical and thermal stresses can be used to assess microvascular reactivity and risk of diabetic foot ulcers.

Comparison of muscle and skin perfusion over the ischial tuberosities in response to wheelchair tilt-in-space and recline angles in people with spinal cord injury.

OBJECTIVE: To compare the efficacy of wheelchair tilt-in-space and recline on enhancing muscle and skin perfusion over the ischial tuberosities in people with spinal cord injury (SCI). DESIGN: Repeated-measures and before-after trial design. SETTING: University research laboratory. PARTICIPANTS: Power wheelchair users with SCI (N=20). INTERVENTIONS: Six combinations of wheelchair tilt-in-space and recline angles were presented to participants in a random order. The testing protocol consisted of a baseline 5 minutes sitting with no tilt/recline and 5 minutes positioned in a tilted and reclined position at each of 6 conditions, including: (1) 15° tilt-in-space and 100° recline, (2) 25° tilt-in-space and 100° recline, (3) 35° tilt-in-space and 100° recline, (4) 15° tilt-in-space and 120° recline, (5) 25° tilt-in-space and 120° recline, and (6) 35° tilt-in-space and 120° recline. MAIN OUTCOME MEASURES: Muscle and skin perfusion were assessed by near-infrared spectroscopy and laser Doppler flowmetry, respectively. RESULTS: Muscle perfusion was significantly increased at 25° and 35° tilt-in-space when combined with 120° recline, and skin perfusion was significantly increased at 3 tilt-in-space angles (15°, 25°, 35°) when combined with 120° recline and at 35° tilt-in-space when combined with 100° recline (P<.05). Even in the positions of increased muscle perfusion and skin perfusion (25° and 35° of tilt-in-space combined with 120° of recline), the amount of muscle perfusion change was significantly lower than the amount of skin perfusion change (P<.05). CONCLUSIONS: Our results indicate that a larger angle of tilt-in-space and recline is needed to improve muscle perfusion compared with skin perfusion. A position of 25° tilt-in-space combined with 120° recline is effective in enhancing muscle and skin perfusion of weight-bearing soft tissues at the ischial tuberosities.

Blocking interleukin-1ß induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes.

Diabetes is associated with persistent inflammation and defective tissue repair responses. The hypothesis of this study was that interleukin (IL)-1ß is part of a proinflammatory positive feedback loop that sustains a persistent proinflammatory wound macrophage phenotype that contributes to impaired healing in diabetes. Macrophages isolated from wounds in diabetic humans and mice exhibited a proinflammatory phenotype, including expression and secretion of IL-1ß. The diabetic wound environment appears to be sufficient to induce these inflammatory phenomena because in vitro studies demonstrated that conditioned medium of both mouse and human wounds upregulates expression of proinflammatory genes and downregulates expression of prohealing factors in cultured macrophages. Furthermore, inhibiting the IL-1ß pathway using a neutralizing antibody and macrophages from IL-1 receptor knockout mice blocked the conditioned medium-induced upregulation of proinflammatory genes and downregulation of prohealing factors. Importantly, inhibiting the IL-1ß pathway in wounds of diabetic mice using a neutralizing antibody induced a switch from proinflammatory to healing-associated macrophage phenotypes, increased levels of wound growth factors, and improved healing of these wounds. Our findings indicate that targeting the IL-1ß pathway represents a new therapeutic approach for improving the healing of diabetic wounds.