Biomedical Engineering Reference
In-Depth Information
the blood, for as long as possible in order to achieve the maximum amount of accumula-
tion at the target site. Investigation into the stability/retention time of the nanocarrier in
circulation in vivo , the degree of platelet aggregation, and the induction of red blood cell
lysis should all be evaluated in order to establish an accurate profile of how the material/
nanocarrier interacts with blood (Wehrung et al., 2012a,b,c, 2013). Blood stability/reten-
tion time studies can also be used to obtain biodistribution data.
Macrophage activation : Activation of macrophages can be assessed in vitro through moni-
toring reactive oxygen species (ROS) production or nitrite production (Wehrung et  al.,
2012a,b,c, 2013).
Cytotoxicity : Cytotoxicity is most commonly assessed through the MTT assay (Wehrung
et al., 2012c, 2013). Alternative assays such as the lactate dehydrogenase (LDH) assay can
also be employed in order to differentiate apoptosis from necrosis (Mrakovcic et al., 2013).
Inlammatory response : Measurement of cytokine release via enzyme-linked immuno-
sorbent assay (ELISA) is a simple and reliable way to assess an inflammatory response
in vitro or in vivo (Wehrung et al., 2013). Additionally, the in vitro macrophage activation
assays noted earlier have also been used to investigate a material's potential to generate
an inflammatory response. Histological examination of tissues following hematoxylin and
eosin (H&E) staining (Wehrung et al., 2013) or the cage implant system are also estab-
lished methods (Koschwanez and Reichert, 2007).
Tissue-speciic toxicity : Histological examination of specific tissues coupled with monitor-
ing changes in serum biochemical markers such as alanine aminotransferase (ALT) and
creatinine have been used for identifying tissue-specific toxicity (Wehrung et al., 2013).
Carcinogenicity/mutagenicity : The Ames test as well as the Comet assay are the preferred
methods for investigation into a novel material's carcinogenicity/mutagenicity (Onuki
et al., 2008; Tice et al., 2000).
Nanocarrier stability in biological conditions : Particle size measured via dynamic light
scattering techniques following incubation in biological fluids (e.g., serum, plasma, tissue
extracts) or in simulate biological conditions (e.g., fetal bovine serum, PBS, Dulbecco's
Modified Eagle Medium) is a simple and effective way to ensure the stability of nanocar-
riers once exposed to a biological environment (Wehrung et al., 2012a,b,c) . The adsorption
of proteins as well as the high salt concentrations found in biological fluids can quickly
change a nanocarrier's zeta potential, thereby causing a loss of particle stability and
allowing particle agglomeration (Ortis-Gil et al., 2013). Particle agglomeration can cause
drastic changes in the biodistribution/pharmacokinetic profile of the nanocarriers, and in
some cases allow large enough aggregates to form that occlusion of the microvasculature
becomes a serious safety concern.
4.7 PERSPECTIVES ON THE FIELD OF STIMULI-RESPONSIVE BIOMATERIALS
The ideal properties of any stimuli-responsive system are (i) biocompatibility of the system (mate-
rial before and after stimulus exposure, as well as the stimulus required for activation), (ii) biode-
gradability, (iii) efficient and rapid response to the stimulus, (iv) high drug-loading efficiency, and
(v) minimal premature drug leakage (e.g., drug release before system activation). While the majority
of publications evaluate their novel systems for most of the aforementioned criteria, biocompat-
ibility is frequently not evaluated or only minimally evaluated (Tables 4.1 and 4.2). This trend is a
grievous oversight, since biocompatibility is absolutely essential if a stimuli-responsive material is
to translate into a clinically relevant solution. The majority of published works rely solely on in vitro
testing—primarily though the MTT assay—and use a prohibitively limited number of time points
and concentrations in order to evaluate biocompatibility. More detailed studies are required in order
to ensure that these new materials are in fact biocompatible. Additionally, many investigators do
not investigate the biocompatibility of the poststimulus material(s), which may not be biocompatible
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