Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

Oxidative stress and diabetic complications

Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling For a wound to heal successfully, all four phases must occur in the proper sequence and time frame Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds

Factors Affecting Wound Healing

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion

Stromal cell-derived factor 1 (SDF-1) or C-X-C motif chemokine 12 (CXCL12) is a highly potent chemoattractant and paracrine protein with critical roles in embryogenesis and hematopoiesis, as well as postnatal tissue repair and regeneration. It acts through the chemokine receptor 4 (CXCR4) and CXCR7 receptors to mediate chemotactic processes including cell signaling and the expression of adhesion molecules, proteinases, and angiogenic factors. During embryogenesis, embryonic stem cells expressing CXCR4 rely on SDF-1 gradients to guide their migration to their target tissues. In the postnatal period, SDF-1 is best known for governing the hematopoietic stem cell (HSCs) niche in the bone marrow (BM) and facilitating the engraftment of transplanted HSCs. More recently, its role in tissue repair has begun to be elucidated. Tissue injury and subsequent hypoxia leads to a hypoxia-inducible factor 1 (HIF-1) mediated increase in endothelial expression of SDF-1. The resultant intravascular SDF-1 gradient recruits hematopoietic lineage cells and lineage negative cells to the site of injury. Endothelial expression of SDF-1 also influences the behavior of tissue-resident cells, promoting proliferation and migration and potentiating paracrine activity. The various downstream effects of SDF-1 expression act in concert to promote neovascularization and tissue regeneration. Impaired regenerative capacity in the setting of aging and disease states such as diabetes is partly due to deficiencies in SDF-1 signaling. Conversely, the unregulated tissue generation of cancer appears to rely on overexpression of SDF-1. Understanding these pathways and their molecular regulation will inform the development of novel targeted therapies across the spectrum of tissue homeostasis.

Stromal Cell-Derived Factor 1 (SDF-1) Signaling and Tissue Homeostasis

A interesting exchange occurred during the Technology Innovation in Plastic Surgery meeting in San Francisco in 2010. It occurred during a panel on aesthetic lasers, an area in which high-level clinical evidence is lacking. The chief executive officer of a major laser company was on the podium and facing tough questions about the absence of data to support his company’s products. Finally, one of the surgeons in the audience asked, “Why don’t you at least try to generate some clinical evidence for your products?” The answer surprised many of us. The chief executive officer responded bluntly along the lines of, “We will generate clinical evidence when you demand it. As long as you are buying products with no data, why would we provide it?” In retrospect, I think the chief executive officer was making the point that if physicians are willing to spend hundreds of thousands of dollars on products with no clinical evidence, why should companies go to the expense of generating high-level clinical data? It is never sound business practice to spend money on things that do not create shareholder value, and if physicians do not truly care about clinical data, why would we expect companies to provide it? As much as we like to think of ourselves as dispassionate surgeon-scientists, the reality of how we make decisions to purchase a product is more complex than simply an analysis of the clinical data. Factors such as longstanding relationships with salespeople, giveaways, revenue upside, the value of the technology in practice marketing, and demand from patients all factor into our decision-making. Thus, it should not surprise us that many businesses with finite resources devote most of their efforts to sales and marketing, often at the expense of generating high-level clinical data. These companies are simply responding to what “works” in terms of moving product off the shelf. Until we demand better clinical evidence, we should not expect it. However, how do we “demand” better clinical evidence? The most effective way to change corporate behavior is not through phone calls, position papers, or the professional societies, but through purchasing decisions. The power of the pocketbook is the greatest weapon we have. Supporting companies that provide high-level evidence, and ignoring companies that do not, would send a powerful message that would not be ignored by the private sector. Our purchasing decisions are the most powerful lever we have to control the evolution of new technologies. Silicone sheeting is not a new technology. It has been around for over 30 years,1 but the level of evidence regarding its clinical effectiveness remains low. The Cochrane Collaboration is a large, international, nonprofit organization dedicated to reviewing the efficacy of health care interventions.2 It produces monographs known as Cochrane Systematic Reviews, which are metaanalyses of all the clinical evidence regarding a given technology. In 2013, the Cochrane Systematic Review on Silicone Sheeting reviewed over 20 randomized controlled trials containing nearly 1000 patients and concluded that “it is unclear whether silicone sheeting helps prevent abnormal scarring or is effective in treating abnormal scars.”3 Moreover, it stated that most of the studies identified were of “poor quality” and recommended that further trials be performed that were objective, blinded, standardized, and of at least 12 months’ duration.

Discussion: No Efficacy for Silicone Gel Sheeting in Prevention of Abnormal Scar Formation in Children with Cancer

This invention relates generally to threads of hyaluronic acid, methods of making such threads and uses thereof, for example, in aesthetic applications (e.g., facial contouring, soft tissue augmentation products), surgery (e.g., sutures), drug delivery, negative pressure wound therapy, moist wound dressing, and the like.

Threads of cross-linked hyaluronic acid and use thereof

A rare case of Wohlfahrtiimonas chitiniclastica infection in California.

The role of the plastic surgeon in oncologic breast reconstruction is to provide a thorough presentation of reconstructive options to the patient and to coordinate closely with the general surgeon, medical oncologist, and radiation oncologist to perform breast reconstruction in the optimal fashion. Breast reconstruction is meant to restore the natural form of the breast and provide a psychological benefit to the patient. It is important to note that not all options are suitable for every patient. Multiple factors need to be considered such as the patient’s body habitus, available donor tissues, lifestyle, recreational and occupational activities, surgeon and patient preference, and need for adjuvant treatment. Therefore, the timing and type of reconstruction must be made after a thorough discussion between the plastic surgeon, the patient, and the patient’s care team.

Geoffrey C. Gurtner

Papers

Stromal Cell-Derived Factor 1 (SDF-1) Signaling and Tissue Homeostasis

Discussion: No Efficacy for Silicone Gel Sheeting in Prevention of Abnormal Scar Formation in Children with Cancer

Threads of cross-linked hyaluronic acid and use thereof

A rare case of Wohlfahrtiimonas chitiniclastica infection in California.

Oncologic Breast Reconstruction: Principles and Practice