1. Introduction

Nanostructured materials are defined as possessing one of their dimensions ranging from 1 to 100 nm, according to the American Society for Testing and Materials (ASTM) international standards definition [1]. For nanoparticles (NPs), which can be of more or less spherical or cubical shape, two dimensions are required to be within this range. In contrast, the shape of nanorods (NRs) is in one dimension much larger than in the others. For a small aspect ratio (<10) both their length and diameter are in the nanoscale, whereas NRs with a large aspect ratio (>10) only have their diameter within this scale, and they are often called "nanowires" (NWs). Nanostructures within this specific size scale show unique size-dependent optical, magnetic, catalytic and electrochemical properties, among others, as well as high surface to volume ratios. Moreover, their shape, surface chemistry and chemical composition can be used to tailor-specific properties, making nanostructures highly versatile for different applications [2, 3].

The size scale of nanostructures is within the range of several biomolecules, such as proteins and antibodies, allowing specific interactions to occur between them. This, when coupled with the high surface to volume ratios and tunable sizes and properties, makes nanostructures prime candidates for biomedical applications such as imaging, drug delivery and therapy [4–6]. Examples of applications include the use of NPs as magnetic resonance imaging (MRI) contrast agents [7, 8], tissue engineering [9–11], as well as the recent focus on hyperthermia and cancer cell eradication with the use of NPs and NRs [12–17]. Such applications, if they are aimed for a clinical setting, ultimately require a direct NP/NR exposure in the form of ingestion or intravenous delivery into the body. Naturally, there is a rigorous testing required before any new drug formulation is approved for clinical use in order to ensure their safety and effectiveness. Currently, very few NPs-based drugs have been approved by the Food and Drug Administration and are commercially available. Examples include GastroMARK, used as an MRI contrast agent to enhance the delineation of the bowel, and ferumoxytol, an iron-replacement formulation approved for adults with chronic kidney disease with an iron deficiency [18].

NPs of different materials, as well as carbon nanotubes (CNTs), whereas the latter is a more indepth review of the internalization, activated signaling pathways and cellular response of

Figure 1. Schematic of the pathways for intracellular uptake of different materials and structures.

Here, we review relevant studies assessing the in vitro cytotoxicity of both nanoparticles (NPs) and nanowires (NWs)/nanorods (NRs) with the potential to be used in biomedical applications. Due to their prevalence within the applied nanomaterials in biomedicine, this chapter covers various materials from four different classes (on Scopus almost 50% of all publications related to cytotoxicity, since the year 2000, fall within these materials) that are typically considered in the context of nanomaterials for biomedical applications. The first part of this chapter covers nonmagnetic metals and magnetic materials, while the second part covers carbon structures and semiconductors. An overview of the materials and structures covered, together

Carbon nanostructures include a broad diversity of carbon allotropes that differ from pristine diamond and graphite. Carbon has been used in many technological applications, exploiting its capability of forming networks composed exclusively of C-atoms with the same electronic

that can be constructed [26]. Since the synthesis of the first carbon nanostructures, such as fullerene C60 (0D) [27] and CNTs (1D) [28] (Figure 2), there has been a tremendous effort for understanding the properties of these nanomaterials and for exploring the broad range of applications in which they can be used. Carbon-based nanomaterials (CNMs) have created a great deal of interest in various applications such as optical imaging [29], drug and gene delivery [30], and nanotherapeutics [31, 32] due to their excellent mechanical, optical and electrical



Review of In Vitro Toxicity of Nanoparticles and Nanorods—Part 2

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with the various intracellular uptake mechanisms, is given in Figure 1.

different kinds of NPs.

2. Carbon nanostructures

configuration or hybridizing configurations sp3

Within this scope, biocompatibility and cytotoxicity data are of paramount importance to evaluate the potential of nanostructures for biomedical applications. Nanostructures are normally engineered to interface and target-specific cells or tissues to execute their functions, raising questions about their toxicological effects. For instance, there are several characteristics involved in the toxicity of fiber-like nanomaterials, such as shape, length, chemical composition, agglomeration and purity, making them suitable to fit the "fiber toxicological paradigm" according to the World Health Organization (WHO) criteria used to describe the toxicity of asbestos fibers [19]. Further, nanostructures are usually tuned for biocompatibility on top of the desired biomedical function, with the most relevant aspects that influence their toxicity being the material [20], size and shape [21], surface charge [22] and surface functionalization [23]. In vitro studies, while not able to give a complete insight into the biocompatibility of nanostructures, have a high importance, due to their easy implementation, and provide valuable cytotoxicology data regarding the safety of the use of nanostructures in biomedical applications. Previously published reviews regarding the biosafety of nanostructures include that of Lewinski et al. [24] and Zhao et al. [25]. The former focuses mostly on the cytotoxicity of

Figure 1. Schematic of the pathways for intracellular uptake of different materials and structures.

NPs of different materials, as well as carbon nanotubes (CNTs), whereas the latter is a more indepth review of the internalization, activated signaling pathways and cellular response of different kinds of NPs.

Here, we review relevant studies assessing the in vitro cytotoxicity of both nanoparticles (NPs) and nanowires (NWs)/nanorods (NRs) with the potential to be used in biomedical applications. Due to their prevalence within the applied nanomaterials in biomedicine, this chapter covers various materials from four different classes (on Scopus almost 50% of all publications related to cytotoxicity, since the year 2000, fall within these materials) that are typically considered in the context of nanomaterials for biomedical applications. The first part of this chapter covers nonmagnetic metals and magnetic materials, while the second part covers carbon structures and semiconductors. An overview of the materials and structures covered, together with the various intracellular uptake mechanisms, is given in Figure 1.
