A future for in vitro models in nanoparticle studies

As a result of the rapid expansion in the use of nanoparticles (NPs) in recent years, it is imperative that we advance our understanding of NP interactions with biological systems in order to establish safety standards and improve the design of nanomaterials. Such mechanisms can of course be investigated in in vivo systems, however the demand and need for in vitro experimental models is increasing. With the introduction of new legislation designed to limit the use of animal models in toxicological studies in industrial settings [1], researchers are being forced to design and validate novel in vitro methods to perform these experiments. Many innovative approaches have been used to develop new models and improve existing ones. In comparison to in vivo assays, they are generally faster to run, more cost effective and often relatively simple thus allowing for well controlled experiments with easily interpreted results. These features make them ideal for running large scale screening studies, which is of particular value for the field of nanotechnology considering the huge numbers of new NPs varying in size, composition, formulation etc. In addition, the use of human derived cells in in vitro models can make them more representative of the human response to NPs as opposed to animal models. An excellent example of a validated in vitro model is that of EpiDerm™ [2], a normal human 3D model of epidermal tissue approved by the EU for full replacement of animal models in skin irritation assays. This model has already been used for the screening of transdermal NP delivery [3].

Obviously there are also disadvantages to the use of in vitro models, a primary one being the inability to recapitulate the complex interactions between cells and organs occurring in vivo since the models are limited to only one or a few different cell types. While in vitro models can be beneficial for investigating whether NPs can cross cellular barriers, studies of overall NP toxicological and pharmacological kinetics are more limited to animal models. The relevance of in vivo experiments however depends on the biological system being investigated and the species used. For example, our lab is interested in the placenta which is the most species-specific mammalian organ so extrapolating information from in vivo studies to the human situation is not straightforward due to distinct differences in placental structure. In vitro models of the placenta are therefore very useful for the study of NP-placenta interactions. However there are currently no widely used and validated models of the placenta made from human primary trophoblasts (the cells which make up the placental barrier). This is mainly because primary trophoblasts do not proliferate in vitro and also the placental barrier structure changes during pregnancy making it difficult to model. Our lab, in collaboration with Prof Akashi laboratory at University of Osaka, has recently developed a novel approach to produce primary trophoblast barrier models in vitro (paper submitted). For the first time, NP interactions with a confluent human trophoblast barrier can be investigated in vitro. We hope to use this model in combination with ex vivo and in vivo experimental systems to study how NPs interact with the placenta and how these interactions can affect the developing fetus.

To summarise, in vitro models provide a beneficial tool for the study of NP interactions with biological systems. They possess many benefits making them in some ways superior to in vivo models and by using them in conjunction with in vivo assays, they can provide an invaluable link between animal models and humans.

Catherine Gilmore
Pathchooser Fellow
University of Bristol

References

  1. Anadón A, Martínez MA, Castellano V, Martínez-Larrañaga MR. (2014) The role of in vitro methods as alternatives to animals in toxicity testing. Expert Opin Drug Metab Toxicol. 10(1):67-79.
  2. Cotovio J, Grandidier MH, Portes P, Roguet R, Rubinstenn G. (2005) The in vitro skin irritation of chemicals: optimisation of the EPISKIN prediction model within the framework of the ECVAM validation process. Altern Lab Anim. 33(4):329-49.
  3. Murthy PB, Kishore AS, Surekha P (2012) Assessment of in vitro skin irritation potential of nanoparticles: RHE model. Methods Mol Biol. 926:219-34.
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