Residual Limb Health and Prosthetics

The residual limb of individuals with lower limb loss is dynamic tissue that is susceptible to both acute and chronic changes to limb volume and health over time. Changes in residual limb volume that affect socket fit may contribute to maladaptive gait patterns and deleterious changes to the socket/limb interface that increase harmful shear stress and contributes to residual limb skin injury. Current socket systems are static and lack the ability to provide end-users and prosthetists with patient-centric data about changes in socket fit over time. There is a need for objective clinical decision-making that results in greater prosthesis usage, improved residual limb health, and better comfort ratings for end-users. Among the socket systems available in the market, the elevated vacuum suspension system improves residual limb skin oxygenation, attenuates socket-induced reactive hyperemia and preserves skin barrier function. This suggests that such a system is compatible with imparting physiological benefits to the residual limb in people with lower limb amputations

Vitamin E sensitive genes in the developing rat fetal brain: a high-density oligonucleotide microarray analysis

AbstractVitamin E (tocopherols and tocotrienols) is essential for normal neurological function. Recently we have reported that the neuroprotective properties of tocotrienols are much more potent than that of the widely studied tocopherols (Sen, C.K., Khanna, S., Roy, S. and Parker, L. (2000) J. Biol. Chem. 275, 13049–13055). The objective of this study was to evaluate whether (i) oral supplementation of tocotrienols during pregnancy is bioavailable to fetal and mother brains; (ii) short-term change in dietary vitamin E levels of pregnant rats influences gene expression profile of developing fetal brains. We report that dietary tocotrienol is bioavailable to both mother and fetal brains. The enrichment is more in fetal brain tissue. Using a GeneChip microarray expression profiling approach we have identified a specific set of vitamin E sensitive genes in the developing rat fetal brain

Sociogenomic Approach to Wound Care: A New Patient-Centered Paradigm

Psychoneuroendocrinology studies provided first insight into social determinants of wound healing. Social stressors impede wound healing. In 2005, we first reported that the transcriptome of wound-site neutrophil is highly responsive to psychological stress in young men. Bioinformatics processing of transcriptome-wide data from neutrophils provided first insight into social transduction pathways relevant to wound healing. In 2010, Idaghdour et al. presented striking evidence demonstrating that genetic factors are responsible for only 5% of the variation in genomic expression. In contrast, the living environment of the individual, urban or rural, was responsible for as much as 50% of such variation. Genetic and environmental factors acted in a largely additive manner. This observation may be credited as the foundation stone of human social genomics. The environment of a patient, including social factors, influences gene expression relevant to wound healing. The nonhealing wound itself and its worsening outcome, including pain, are likely to cause stress. Conversely, positive social interactions may circumvent barriers to wound healing. Thus, interventions directed at the social environment of a wound care patient are likely to help manage wound chronicity. The genomic and related Big Data technology platforms have vastly improved during the past 5 years during which these technologies have also become widely accessible and affordable. Thus, this is the right time to revisit the choice of technologies for the study of social genomics of wound healing. Against the backdrop of our current understanding of the mechanisms of wound healing, such precision approach is likely to transform wound care and its outcomes making it patient-centered and, therefore, more effective

Nutrigenomic Analysis of Diet-Gene Interactions on Functional Supplements for Weight Management

Recent advances in molecular biology combined with the wealth of information generated by the Human Genome Project have fostered the emergence of nutrigenomics, a new discipline in the field of nutritional research. Nutrigenomics may provide the strategies for the development of safe and effective dietary interventions against the obesity epidemic. According to the World Health Organization, more than 60% of the global disease burden will be attributed to chronic disorders associated with obesity by 2020. Meanwhile in the US, the prevalence of obesity has doubled in adults and tripled in children during the past three decades. In this regard, a number of natural dietary supplements and micronutrients have been studied for their potential in weight management. Among these supplements, (–)-hydroxycitric acid (HCA), a natural extract isolated from the dried fruit rind of Garcinia cambogia, and the micronutrient niacin-bound chromium(III) (NBC) have been shown to be safe and efficacious for weight loss. Utilizing cDNA microarrays, we demonstrated for the first time that HCA-supplementation altered the expression of genes involved in lipolytic and adipogenic pathways in adipocytes from obese women and up-regulated the expression of serotonin receptor gene in the abdominal fat of rats. Similarly, we showed that NBC-supplementation up-regulated the expression of myogenic genes while suppressed the expression of genes that are highly expressed in brown adipose tissue in diabetic obese mice. The potential biological mechanisms underlying the observed beneficial effects of these supplements as elucidated by the state-of-the-art nutrigenomic technologies will be systematically discussed in this review

Collagen in Wound Healing

Normal wound healing progresses through inflammatory, proliferative and remodeling phases in response to tissue injury. Collagen, a key component of the extracellular matrix, plays critical roles in the regulation of the phases of wound healing either in its native, fibrillar conformation or as soluble components in the wound milieu. Impairments in any of these phases stall the wound in a chronic, non-healing state that typically requires some form of intervention to guide the process back to completion. Key factors in the hostile environment of a chronic wound are persistent inflammation, increased destruction of ECM components caused by elevated metalloproteinases and other enzymes and improper activation of soluble mediators of the wound healing process. Collagen, being central in the regulation of several of these processes, has been utilized as an adjunct wound therapy to promote healing. In this work the significance of collagen in different biological processes relevant to wound healing are reviewed and a summary of the current literature on the use of collagen-based products in wound care is provided

Novel Bacterial Diversity and Fragmented eDNA Identified in Hyperbiofilm-Forming Pseudomonas aeruginosa Rugose Small Colony Variant

Pseudomonas aeruginosa biofilms represent a major threat to health care. Rugose small colony variants (RSCV) of P. aeruginosa, isolated from chronic infections, display hyperbiofilm phenotype. RSCV biofilms are highly resistant to antibiotics and host defenses. This work shows that RSCV biofilm aggregates consist of two distinct bacterial subpopulations that are uniquely organized displaying contrasting physiological characteristics. Compared with that of PAO1, the extracellular polymeric substance of RSCV PAO1ΔwspF biofilms presented unique ultrastructural characteristics. Unlike PAO1, PAO1ΔwspF released fragmented extracellular DNA (eDNA) from live cells. Fragmented eDNA, thus released, was responsible for resistance of PAO1ΔwspF biofilm to disruption by DNaseI. When added to PAO1, such fragmented eDNA enhanced biofilm formation. Disruption of PAO1ΔwspF biofilm was achieved by aurine tricarboxylic acid, an inhibitor of DNA-protein interaction. This work provides critical novel insights into the contrasting structural and functional characteristics of a hyperbiofilm-forming clinical bacterial variant relative to its own wild-type strain

A Modified Collagen Dressing Induces Transition of Inflammatory to Reparative Phenotype of Wound Macrophages

Collagen containing wound-care dressings are extensively used. However, the mechanism of action of these dressings remain unclear. Earlier studies utilizing a modified collagen gel (MCG) dressing demonstrated improved vascularization of ischemic wounds and better healing outcomes. Wound macrophages are pivotal in facilitating wound angiogenesis and timely healing. The current study was designed to investigate the effect of MCG on wound macrophage phenotype and function. MCG augmented recruitment of macrophage at the wound-site, attenuated pro-inflammatory and promoted anti-inflammatory macrophage polarization. Additionally, MCG increased anti-inflammatory IL-10, IL-4 and pro-angiogenic VEGF production, indicating a direct role of MCG in resolving wound inflammation and improving angiogenesis. At the wound-site, impairment in clearance of apoptotic cell bioburden enables chronic inflammation. Engulfment of apoptotic cells by macrophages (efferocytosis) resolves inflammation via a miR-21-PDCD4-IL-10 pathway. MCG-treated wound macrophages exhibited a significantly bolstered efferocytosis index. Such favorable outcome significantly induced miR-21 expression. MCG-mediated IL-10 production was dampened under conditions of miR-21 knockdown pointing towards miR-21 as a causative factor. Pharmacological inhibition of JNK attenuated IL-10 production by MCG, implicating miR-21-JNK pathway in MCG-mediated IL-10 production by macrophages. This work provides direct evidence demonstrating that a collagen-based wound-care dressing may influence wound macrophage function and therefore modify wound inflammation outcomes

Electroceutical Management of Bacterial Biofilms and Surgical Infection

Significance: In the host–microbe microenvironment, bioelectrical factors influence microbes and hosts as well as host–microbe interactions. This article discusses relevant mechanistic underpinnings of this novel paradigm. It also addresses how such knowledge may be leveraged to develop novel electroceutical solutions to manage biofilm infection. Recent Advances: Systematic review and meta-analysis of several hundred wound studies reported a 78.2% prevalence of biofilms in chronic wounds. Biofilm infection is a major cause of delayed wound healing. In the host–microbe microenvironment, bioelectrical factors influence interactions between microbes and hosts. Critical Issues: Rapid biological responses are driven by electrical signals generated by ion currents moving across cell membranes. Bacterial life, growth, and function rely on a bioelectrical milieu, which when perturbed impairs their ability to form a biofilm, a major threat to health care. Electrokinetic stability of several viral particles depend on electrostatic forces. Weak electrical field strength, otherwise safe for humans, can be anti-microbial in this context. In the host, the electric field enhanced keratinocyte migration, bolstered immune defenses, improved mitochondrial function, and demonstrated multiple other effects consistent with supporting wound healing. A deeper mechanistic understanding of bioelectrical principles will inform the design of next-generation electroceuticals. Future Directions: This is an opportune moment in time as there is a surge of interest in electroceuticals in medicine. Projected to reach $35.5 billion by 2025, electroceuticals are becoming a cynosure in the global market. The World Health Organization reports that more than 50% of surgical site infections can be antibiotic resistant. Electroceuticals offer a serious alternative

A surfactant polymer wound dressing protects human keratinocytes from inducible necroptosis

Chronic wounds show necroptosis from which keratinocytes must be protected to enable appropriate wound re-epithelialization and closure. Poloxamers, a class of synthetic triblock copolymers, are known to be effective against plasma membrane damage (PMD). The purpose of this study is to evaluate the efficacy of a specific poloxamer, surfactant polymer dressing (SPD), which is currently used clinically as wound care dressing, against PMD in keratinocytes. Triton X-100 (TX100) at sub-lytic concentrations caused PMD as demonstrated by the efflux of calcein and by the influx of propidium iodide and FM1-43. TX100, an inducer of necroptosis, led to mitochondrial fragmentation, depletion of nuclear HMGB1, and activation of signaling complex associated with necroptosis (i.e., activation of RIP3 and phosphorylation of MLKL). All responses following exposure of human keratinocytes to TX100 were attenuated by pre- or co-treatment with SPD (100 mg/ml). The activation and translocation of phospho-MLKL to the plasma membrane, taken together with depletion of nuclear HMGB1, characterized the observed cell death as necroptosis. Thus, our findings show that TX100-induced plasma membrane damage and death by necroptosis were both attenuated by SPD, allowing keratinocyte survival. The significance of such protective effects of SPD on keratinocytes in wound re-epithelialization and closure warrant further studies

Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice

Background: Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing. Methodology/Principal Findings: Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from proinflammatory to an anti-inflammatory mode. Conclusions/Significance: Taken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing