**5. Physiological impact due to nanomaterials**

Nanostructured biomaterials are being analyzed in detail currently for regenerative applications. However, their physiological impact due to the prolonged presence of these foreign agents within the body or their degradation byproducts can be broadly divided as the impact of ROS generation and oxidative stress, inflammation and cellular injury due to nanoparticle dissolution.

#### **5.1 Reactive oxygen species (ROS) generation and oxidative stress**

Nanoparticles, including transitional metals, have been reported to be oxidized and release reactive oxygen species of which hydroxyl radicals are considered to cause maximum damage, including affecting cell signaling pathways and affecting the cellular lipids, protein production, alteration of DNA and gene transcription [38]. Also inflammatory cells including neutrophils and macrophages are attracted by phagocytosis of these nanoparticles which in turn leads to the production of proinflammatory cytokines and oxidative stress [38]. Researchers have reported the extent and severity of inflammation is dependent on characteristics of the nanoparticles such as size and shape.

In response to low levels of oxidative stress generated by nanoparticles, the cells release antioxidants such as ferritin, N-acetylcysteine (NAC), which nullify the oxidative stress; however cellular damage occurs due to excessive reactive species [38].

#### **5.2 Inflammation**

Deng et al. reported that the decreased size of poly aryl acid-coated gold nanomaterials (<20 nm) have been associated with the activation of the Mac-1 receptor of the monocytes [39]. This in turn, leads to upregulation of the proinflammatory cytokines via the NF-κB pathway. Poly(d,L-lactide-co-glycolic acid) (PLGA) nanoparticles 75 nm or lesser reported lesser PMN in bronchial lavage fluid than in 200 nm size particles. Also, the varying shapes of these nanoparticles have been found to elicit inflammatory responses. Albanese et al. reported that the size and shape of these nanoparticles dictate the ligand and receptor interactions that in turn determine the cellular uptake and the further downstream reactions [40]. However, nanoparticles can be used as drug-delivery agents to suppress these inflammatory reactions.

Nanoporous scaffolds similar in architecture to the native tissues have been found to have lesser associated inflammatory reactions [41]. Silica and hydroxyapatite based nanoporous scaffolds have integrated better than cancellous bone substitutes in association with implant-based in vivo studies. Nanoporous scaffolds made of native matrix proteins or with a coating of bioinert polymers (such as poly ethyl glycol PEG) along with sustained release of anti-inflammatory agents and antioxidants would have better integration with host tissues with minimal inflammation.

Certain nanotopographical alterations in these nanomaterials are capable of altering the host inflammatory response attenuating or at other times exacerbating the same [41]. It needs to be understood to ensure successful incorporation of nanomaterials in tissue engineering applications.

#### **5.3 Cellular injury due to nanoparticle dissolution**

Nanoparticle dissolution is a crucial property which determines the extent of its availability, its toxicity and also its impact on the host environment. Their greater surface area leads to increased physical and chemical interactions which leads to dissolution.

It may lead to cell death or in case of non-degradable NP can accumulate within the cells leading to damage. Quantum dots localize in varying cellular locations, Silica (40–80 nm) is deposited in the nucleoplasm, and gold nanoparticles have been found in the major groove of DNA (leading to the formation of human cancer cells) [38]. Nanomaterials have been found to induce autophagy which occurs as a response to the cellular changes in the aftermath of oxidative stress.

In vitro studies have shown that cationic Polyamidoamine (PAMAM) dendrimers are more likely to lead to autophagy than the anionic dendrimers [41]. Nanomaterials are thought to alter the autophagic degradation activity which might lead to toxicity [42]. Gold nanoparticles as compared to Silicon dioxide nanoparticles have been found to

*Toxicity Evaluation and Biocompatibility of Nanostructured Biomaterials DOI: http://dx.doi.org/10.5772/intechopen.109078*

lower the lysosomal degradation which in turn affects the normal functioning of the cells. Atomic Force Microscopy studies on osteoblast cells reveal alterations in osteoblast cell membranes leading to changes in cell adhesion in response to nanoparticles [43]. Also, Bhabra et al. reported that nanoparticles (Cobalt-chromium) also indirectly affect the cells, including DNA damage without even permeating through the cellular barrier [44].
