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

Vascularized composite allotransplantation (VCA) enables surgeons to address complex problems that exceed the possibilities of traditional autologous reconstruction. However, logistical and immunologic challenges currently limit the widespread application of VCA. Recent breakthroughs in the field of stem cells and tissue engineering have direct implications for the advancement of VCA. Specifically, the use of bioreactors may prolong ex vivo allograft survival and enable allograft modulations that mitigate immunogenicity and enhance graft function. Additionally, novel approaches utilizing bioreactor systems for stem cell seeding of vascularized bioscaffolds provide a blueprint for the de novo generation of complex tissues. These promising bioreactor-based strategies have the potential to expand the reconstructive applications of VCA, and could one day allow the fabrication of customized complex tissue grafts.

Organ-level tissue engineering using bioreactor systems and stem cells: implications for transplant surgery.

This chapter broadly reviews the use of stem cells as a means to accelerate wound healing, focusing first on the properties of stem cells that make them attractive agents to influence repair, both alone and as vehicles for growth factor delivery. Major stem cell reservoirs are described, including adult, embryonic, and induced pluripotent cell sources, outlining the advantages and limitations of each source as wound healing agents, as well as the possible mechanisms responsible for wound healing acceleration. Finally, the chapter includes a materials and methods section that provides an in-depth description of adult tissue harvest techniques.

Adult stem cells in small animal wound healing models.

Acellular dermal matrices (ADM) have reportedly been associated with postoperative complications following breast reconstruction. The purpose of this study was to identify risk factors predictive of major postoperative complications after staged implant-based breast reconstruction with ADM. A retrospective study of all patients who underwent implant-based breast reconstruction with AlloDerm between 2013 and 2017 was conducted. Demographic information, procedural data, and postoperative complications were retrieved. The main objective was to analyze patient and procedural factors associated with the occurrence of major complications, including postoperative readmission and loss of reconstruction. A total of 166 patients (288 breasts) were included. Major complications were noted in 19.9%. The overall rate of infection and mastectomy skin necrosis was 16.9% and 6.6%, respectively. Readmission occurred in 16.3% and loss of reconstruction occurred in 8.4% of patients. Risk factors for major complications included body mass index (BMI) >27.0 kg/m2 (OR 2.46; p = 0.041), higher tissue expander volume (p = 0.049), history of chemotherapy (OR 2.20; p = 0.047) and radiotherapy (OR 2.22; p = 0.040). Loss of reconstruction was associated with a BMI >27.0 kg/m2 (OR 4.00; p = 0.012), tobacco use (OR 6.64, p = 0.006), and higher tissue expander volume (p = 0.035). Similarly, readmission was associated with higher tissue expander volume (p = 0.042). In conclusion, a variety of factors were identified to be associated with major complications, including higher BMI, increased tissue expander volume, as well as history of chemotherapy and radiation. This information is valuable for pre-operative counseling and for future comparative studies between different ADM types.

Identifying risk factors for postoperative major complications in staged implant‐based breast reconstruction with AlloDerm

https://doi.org/10.1016/j.bioactmat.2022.04.004

A bioactive compliant vascular graft modulates macrophage polarization and maintains patency with robust vascular remodeling

The skin is the largest organ in the human body and is constantly exposed to mechanical stress. Various skin diseases and abnormal cutaneous wound healing may be associated with the disruption of the skin's mechanical homeostasis and dysfunctional mechanotransduction. These skin disorders raging from keloid disease to diabetic skin ulcers pose a significant health-care challenge costing the economy billions of dollars every year. Recent advances in our understanding of cellular and molecular aspects of skin mechanotransduction have led to the development of various strategies to modulate the skin's mechanical environment and restore mechanical homeostasis for therapeutic applications. This chapter will discuss current mechanistic insights into the mechanobiology of the skin, how dysfunctional mechanotransduction can lead to skin diseases and abnormal wound healing, and relevant therapeutic strategies.

Geoffrey C. Gurtner

Papers

Organ-level tissue engineering using bioreactor systems and stem cells: implications for transplant surgery.

Adult stem cells in small animal wound healing models.

Identifying risk factors for postoperative major complications in staged implant‐based breast reconstruction with AlloDerm

A bioactive compliant vascular graft modulates macrophage polarization and maintains patency with robust vascular remodeling

Mechanobiology of skin diseases and wound healing