Generation of free radicals and oxidative stress play important roles in the physiological response to engineered biomaterials and nanoparticles. Critical to developing new materials and understanding this process is the ability to detect changes in oxidative stress and the red/ox status of cells. In this chapter, a comprehensive overview of most commonly used methods for detection of oxidative stress is presented. Specifically addressed are issues and limitations related to the choice of model (in vitro vs in vivo studies) and approach (direct detection of free radicals vs detection of indexes of oxidative stress). A comprehensive overview of the literature is provided for some of the classical methods, involving the use of highly fluorescent 2’,7’-dichlorofluorescein, thiobarbituric acid reactive species test, etc., and more modern and sophisticated assays, such as the Seahorse XF, Redox proteomics for the detection of changes of cellar function, oxidative stress in contact with biomaterials and nanoparticles..

Reactive oxygen species (ROS) serve as important mediators and signaling molecules in many biological processes, but their overproduction can cause or exacerbate disease. This has motivated the development of biomaterials that can interact with ROS in a therapeutic capacity. These ROS-sensitive materials have been primarily used in three broad biomedical applications: (1) ROS-mediated intracellular drug release for targeted delivery to highly oxidative phagocytic or cancerous cells, (2) extracellular drug delivery targeted to tissues with elevated levels of ROS, and (3) the formation of ROS-degradable tissue engineering scaffolds. This chapter outlines the chemistry and function of the different oxidatively responsive polymers currently being researched and describes their functionality in various biomedical applications.

Oxidative stress, inflammation, and the respiratory burst occur when phagocytic cells are stimulated to respond to infection or the presence of a foreign material. They are major factors in how the body responds to metallic biomaterials. However, until recently, the study of the biocompatibility of metallic medical devices has focused primarily on the toxicity of metal cations and the generation and consequence of metal-based particle debris resulting from the oxidation side of metal corrosion reactions. In this chapter, the interplay between corrosion and biology is refocused to explore several newly recognized interactions that arise between metals engaging in electrochemical processes (oxidation and reduction associated with corrosion) and the biological system (which is rich in redox processes including respiratory burst and the generation of reactive oxygen species). Reduction reactions at metal surfaces induce cellular apoptosis when cells are cultured directly on cathodically polarized metal surfaces, and inflammatory cells, using ROS and oxidative burst, can corrode implant surfaces in a far more aggressive fashion than was previously understood. Together, these insights expand the concept of biocompatibi­lity for metallic biomaterials in vivo and more clearly define a zone of electrochemical viability (ie, a voltage range within which cells remain viable, and outside of which they die). Overall, the interplay between metals and biology are far more complex than previously appreciated and results in two-way positive feedback between corrosion and biology.

Inflammation occurs after the in vivo introduction of biomaterials as the body responds to the material and the tissue damage caused by the process of implantation. This chapter describes the inflammatory and foreign body responses to biomaterials and the impact of the physicochemical properties of biomaterials on activating this innate response. Also discussed are the roles of reactive oxygen species produced by biomaterials and surrounding tissues on the initiation, propagation, and remedy of inflammation. In doing so, the relationship between inflammation and oxidative stress and how they help propagate each other will be elucidated. An understanding of this relationship will be helpful in developing strategies to mediate foreign body response and its deleterious effects on implanted biomaterials.

Oral mucositis (OM) is a common and one of the most debilitating side effect of anti-cancer chemo- and radiation therapies. The large ulcers of the oral mucosa and unbearable pain leave patients in misery and the lack of efficacious prophylactic or treatment options force interruption of the life-saving cancer therapy. This chapter provides a brief overview of the pathophysiology of OM and the current state of treatments available for OM management. A short discussion about the plethora of therapeutics evaluated, and their general failure to achieve efficacy, has also been included. The primary focus of the chapter is the importance of oxidative stress in OM development and the evidence to support bringing antioxidant therapeutics to the forefront of OM treatment and prevention. Many practical challenges prevent clinical adoption of antioxidants as efficacious therapeutics, and the chapter discusses new drug delivery technologies that are attempting to address these limitations in the context of curcumin as a model antioxidant drug for OM.

In this chapter, an overview will be given of progress in the development of antioxidant polymers and their therapeutic use. Oxidative stress has been identified as a key player in many disease conditions, as well as a result of commonly used implantable biomaterials. Systemic delivery of antioxidants is hampered by poor absorption, loss of bioactivity, limited time frame of effectiveness, and nontargeted lowering of oxidative stress. For this reason, polymers are being developed for localized, sustained antioxidant activity. Antioxidant entrapment in polymers will be discussed, as well as development of polymers with intrinsic antioxidant activity, with an emphasis on the latter.

Radical oxidants, such as superoxide and the hydroxyl radical, play a pivotal role in biology. Technologies that can selectively image radical oxidants in various biological systems can play an important role in biology and medicine. Radical oxidants are critically involved in a wide variety of pathophysiologic events ranging from atherosclerosis to cancer, and radical oxidants are therefore, excellent diagnostic biomarkers for a wide range of diseases. Radical oxidants are also implicated in the efficacy of antibiotics and anticancer drugs, consistently, the radical oxidant probes can be useful in drug discovery process. Radical oxidants are also important in the process of evolution because of their role in DNA mutagenesis and leading to drug resistance. In conclusion, radical oxidants are implicated in over 150 inflammatory diseases and are involved in aging, toxicity, cell growth, signaling, cell differentiation, cell damage, tumor survival and drug efficacy, consequently, there is tremendous interest in imaging radical oxidants in biological systems. Hydrocyanines, therefore, are playing increasingly important role in studying redox and disease biology.

As one of a few successful implantable medical devices, total joint implants are expected to function without deterioration for at least several decades in vivo. The polymeric components of total joint implants, made from medical grade ultrahigh molecular weight polyethylene, are sensitive to oxidative stress during manufacturing, storage, and during the implant’s lifetime. In this chapter, we will briefly describe the inception and evolution of joint implants, their oxidation processes and strategies to protect them against oxidation and oxidative degradation.

With the rapid growth of nanotechnology, a large number of nanomaterials will be developed and produced as new formulations and surface properties to meet novel demands. Therefore, occupational or nonoccupational exposure to nanoparticles is growing, and the potential health impact of these new products cannot be ignored. Until recently, there were no specific regulations on the nanoparticles except existing regulations addressing that same material in bulk form. Exposure to nanoparticles in the air may represent an important preventable cause of both morbidity and mortality for those living in a polluted environment. A common feature of all forms of particle toxicity is the influx of activated inflammatory cells to the lung. Therefore, inflammation is a potential mechanism for the adverse effects of all pathogenic particles and is likely to be an important driver for nanoparticles. In fact, nanoparticles, such as nanocarbon, have been shown to have the ability to cause inflammation in humans, and many nanoparticles have been shown to induce inflammation in animal models by intratracheal instillation or inhalation. Free radicals and oxidative stress have been extensively implicated in the inflammatory effects of nanoparticles. Therefore, oxidative stress is a central hypothetical mechanism for the adverse effects of nanoparticles. This chapter introduces the potential toxic effects of nanoparticles and their mechanisms, and their potential environmental impact.

Oxidative stress occurs due to the imbalance between the production of reactive oxygen species (ROS) and the availability of antioxidants or radical scavengers. The excess ROS produced can either oxidize biomolecules or can structurally modify proteins and genes so as to trigger signaling cascades that can lead to the onset and progression of inflammatory diseases. ROS-induced activation of transcription factors and pro-inflammatory genes lead to the onset of inflammation. Inflammation causes immune cells to secrete various cytokines and chemokines in order to recruit various other immune cells to the site of oxidative stress/infection. Reflexively, an enhanced ROS generation by immune cells at the site of inflammation causes oxidative stress and tissue injury. This interrelation between oxidative stress and inflammation is discussed in the present chapter with a view to highlight the role of “ROS-induced-inflammation” pathways in the progression of several pathologies.