Timing, hosts and locations of (grouped) events of NanoImpactNet

NanoSafetyCluster - Compendium 2012
A major innovative aspect of the InLiveTox project is the
implementation of biological tissue models in a microfabricated
compartmental cell culture system that allows multiple cell
types to be addressed and investigated in combination. This
system will be much easier, more convenient and ethically less
questionable than animal testing, as well as more relevant than
the in vitro single cell /co-culture models currently used. For this
study, applications of the model will focus on NP toxicology, but
the system could also be widely used in various applications of
toxicology and pharmacology.
2 Introduction
Context
Nanotechnology is defined as the ability to create and use
materials, devices and systems with unique properties at the
scale of approximately 1 to 100 nanometres. The use of
nanotechnology in consumer and industrial sectors is expected
to increase significantly in the future. Nanotechnology offers
society the promise of major benefits, but also raises questions
of potential adverse effects. The challenge for health (and
environmental) protection is to ensure that as nanomaterials 1
are developed and used, any unintended consequences of
exposure to humans are prevented or minimised.
In Europe and in the USA, governments, non-governmental
organisations, and others have expressed concern that the
number of consumer products incorporating nanomaterials is
increasing dramatically, that, in many cases, the safety of these
materials has not been demonstrated and that there are still a
large number of unanswered questions. For example, little is
known about the relationship between the physicochemical
characteristics of nanoparticles (NPs) and their ability to cross
cell-barriers and to enter the general circulation, their fate
within the body (toxicokinetics), their subsequent toxic impact,
or the ability of our bodies to defend against such toxic impact.
In order to understand such behaviour and responses, and to
manage the resulting risks, it is essential to investigate the
hazard (toxicology) of the large number of engineered NPs in
different formulations and at different points in their life cycle
(from production to disposal), in relation to different routes of
exposure and different target organs and tissues. The number
of experiments required to address all of these issues is
enormous and so it is essential to develop rapid and reliable
non-animal models to assess NP hazards.
The InLiveTox project has formed an interdisciplinary
consortium at the European level, together with an American
key research group to develop an improved in vitro model for
1
The term nanomaterials refers to engineered
nanomaterials and particles.
NP uptake and the impact of the NP on different cell types,
thereby advancing our understanding of NP toxicity.
Rather than repeat what has been done in the field of aerosol
NPs and lung toxicology, InLiveTox focuses on the impact of NP
exposure via ingestion, in the healthy and diseased (susceptible)
gastrointestinal tract, and the subsequent impact on the
endothelium and liver parenchymal cells (hepatocytes).
Exposure via ingestion is particularly relevant due to the
inclusion of NPs in food, food packaging and in oral medicines.
The key questions pertaining to this research are: (i) How do
these tissues individually respond to NP? (ii) How do the
interactions between the different organs modulate their
individual responses? (iii) How does inflammation affect the
toxicity of NP and their ability cross the intestinal barrier? (iv)
Which physico-chemical characteristics of NP influence their
uptake by intestinal epithelial cells and their subsequent
interactions with the vascular endothelium and liver cells?
Concepts
The origin of the InLiveTox project is the idea of developing a
novel modular microfluidics-based in vitro test system modelling
the response of cells and tissues to the ingestion of NPs. Models
of target tissues such as the gastrointestinal tract, the liver and
the endothelium will be connected to each other via a
microfluidics system, so that knock-on and cross-talk effects
between organs and tissues can be closely monitored.
The innovative aspect of InLiveTox project pertains to the
implementation of biological tissue models in a microfabricated
compartmental cell culture system which allows multiple cell
types to be addressed and interrogated in a single device, the
InLiveTox system. This system will be much more convenient
and ethically less questionable than animal testing, as well as
more relevant than the single /co-culture cell in vitro models
currently used. For this study, the model will focus on NP
toxicology, but the InLiveTox system can also be more widely
used in various applications of toxicology and pharmacology.
Currently, the study of the interaction between organs and
tissues during NP exposure via ingestion is complex and
laborious in vivo, and has not been attempted in vitro except by
InLiveTox partner groups. In vitro test models for nano- or any
other type of toxicology, are either based on one cell type,
crude mixes of different cell types, or transfer of conditioned
medium between different cell types.
The InLiveTox system will be based on the technologies and
tools developed by the different project partners to implement
model biological barriers and tissues in a microfluidics system.
Together, these bring the in vitro system much closer to in vivo
reality and will provide the means to study NP effects in a
healthy or diseased model of ingestion.
3 Objectives
The objectives of the project are
48 Compendium of Projects in the European NanoSafety Cluster