Biomedical Engineering Reference
In-Depth Information
complex biological interaction systems is challenging and long-term testing is not possible
in vitro
[28]. On the other hand,
in vivo
tests allow for the accounting of multiple factors that may affect
the toxicity of the nanomaterials in a biological system. For instance, it has been reported that in
serum, nanoparticles tend to have a “protein corona” formation around their surface, which may
directly impact the properties exhibited by the nanoparticle and the nature of the interactions with
the cell membrane [35]. On the other hand, the interactions of the nanoparticle with the biological
proteins, receptors, and membranes may further complicate the interpretation of
in vivo
results;
thus, thorough characterization is necessary in order to adequately understand the biointeractions
of the nanomaterials. Identifying and understanding the processes and pathways leading to toxicity
in an organism may be challenging in the
in vivo
setting.
The design of the delivery vehicle is another noteworthy component of
in vivo
experiments.
Because of their increased specific surface area and high reactivity, the nanoparticles tend to
agglomerate. Thus, the vehicle is very important in maintaining stable homogeneous solution.
Physiological solutions, the presence of proteins, and pH changes may result in agglomeration,
which may alter the behavior of nanomaterials in a biological system [36]. Specifically for
in vivo
tests, the delivery phase needs to be isotonic and nontoxic with well-dispersed nanoparticles. For
biocompatibility reasons, phosphate-buffered saline solution has been used most commonly for
in vitro
treatments although it may not prevent agglomeration [37]. Other delivery vehicles con-
taining lipids and proteins have been designed and tested; however, the composition of the deliv-
ery vehicle depends more on the specific route of nanomaterial exposure: pulmonary, ingestion,
topical application, and intravenous administration [38]. Another challenge for
in vivo
studying
is determining the treatment dose. It is difficult to determine the exposure concentration due to
many external sources, such as food, air, and the environment; a high treatment dose may not
have relevant physiological consequences. Furthermore, the differences between species and in
animal models require different dosing, and the physiological distinctions are sufficient to yield
results that are different from human subjects. Overall, toxicity from nanomaterials can be most
optimally studied by combining experiments that address multiple components of nanoparticle
properties. The thorough characterization of chemical and physical parameters is necessary
for fully understanding the behavior of nanomaterials in biological systems.
In vitro
studies
allow for the identification of specific pathways involved in metabolism and the extrapolation of
pharmacokinetics through the use of cell proliferation assessments, reactive oxygen and nitro-
gen species generation, apoptosis and necrosis assays, microscopic imaging in tissues, gene
profiling, and genotoxicity evaluations [39].
In vivo
studies are often deemed necessary, as
in
vitro
and
in vivo
studies do not always correlate and published literature findings are often con-
tradicting. This may be due to the need of further developing sophisticated
in vitro
cell culture
systems for the adequate presentation of biological systems, and to address the unique nature of
nanoparticles.
The study of toxicokinetics certainly presents its own challenges of multivariable relationships in
nanomaterial parameters and biological systems. A plethora of studies have been accomplished to
address the question of nanomaterial toxicity; however, owing to the vast number of combinations
and variations, each nanoformulation has to be tested for each biological system individually, as it
is the description of specific parameters and their impact on health that lends the most assistance in
the design of safe nanomaterials. The field of nanotoxicology is still lacking predictive capabilities.
More recently, more studies on the applications of mathematical models using multivariate linear
regression have been published as potentially beneficial methods in planning and directing toxi-
cological studies [40]. Toxicological assessments using theoretical models before the development
of
in vitro
or
in vivo
experiments would allow for the identification of relevant pathways, predic-
tion of toxicity, and determination of toxic dosages. To most effectively harness the ability to test
toxicological properties of nanoparticles in cell lines, mathematical models along with mechanism-
centered high-throughput testing may significantly benefit the further development of the field of
toxicogenomics [41].
