Timing, hosts and locations of (grouped) events of NanoImpactNet
Timing, hosts and locations of (grouped) events of NanoImpactNet
Timing, hosts and locations of (grouped) events of NanoImpactNet
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- to develop <strong>and</strong> validate a novel model for assaying<br />
ingested NP toxicity, the InLiveTox system<br />
- to gain new insights into NP toxicity.<br />
These objectives will be achieved by bringing together<br />
micr<strong>of</strong>luidics technologies with cell culture models <strong>of</strong> human<br />
tissues to produce an in vitro test system that is more<br />
physiologically relevant. The micr<strong>of</strong>luidics system will be flexible<br />
<strong>and</strong> modular so that the complexity <strong>of</strong> the system can be<br />
increased stepwise to include additional cell types, more<br />
complex 3D models <strong>of</strong> tissues, <strong>and</strong> more sophisticated tests <strong>of</strong><br />
cellular responses to the presence <strong>of</strong> nanoparticles. Thus, while<br />
the main focus <strong>of</strong> the project concentrates on cell culture<br />
models <strong>of</strong> healthy tissues, there will also be work on a more<br />
complex model <strong>of</strong> the ‘susceptible’ or inflamed intestinal<br />
epithelium.<br />
The InLiveTox system will be validated using in vivo assays <strong>of</strong><br />
biokinetics <strong>and</strong> toxic response using a rat model. In contrast, the<br />
cell culture models in the InLiveTox system use established<br />
human cell lines. The use <strong>of</strong> human cell lines ensures more<br />
reproducible results <strong>and</strong> a more stable culture system. Great<br />
care is being taken to obtain well-characterised <strong>and</strong><br />
reproducible NP preparations for both in vivo <strong>and</strong> in vitro<br />
experiments, so that relevant <strong>and</strong> useful comparisons can be<br />
made between them.<br />
The consortium has chosen to validate <strong>and</strong> demonstrate the<br />
InLiveTox system by studying a relevant but largely neglected<br />
route <strong>of</strong> entry <strong>of</strong> NPs into the body: ingestion. The cell lines to<br />
be cultured in the InLiveTox system have been chosen as<br />
models for organs <strong>and</strong> tissues <strong>of</strong> particular relevance for<br />
ingestion: the intestinal epithelium, the vascular endothelium<br />
<strong>and</strong> the liver. Similarly, validation assays will focus on NP toxicity<br />
by gavage. In this way, new insights will be generated into NP<br />
toxicity on ingestion, based on both in vivo <strong>and</strong> in vitro data.<br />
4 Scientific/technical methodology <strong>and</strong> work<br />
plan<br />
The organisation <strong>of</strong> the project into different work packages is<br />
shown below.<br />
NanoSafetyCluster - Compendium 2012<br />
PERT diagram showing the structure <strong>of</strong> the project in work<br />
packages <strong>and</strong> the flow <strong>of</strong> results <strong>and</strong> information between the<br />
different work packages<br />
In a first phase <strong>of</strong> the project, in work package 1, a micr<strong>of</strong>luidics<br />
device will be designed <strong>and</strong> fabricated for the simultaneous<br />
culture <strong>of</strong> different cell lines representing the intestinal<br />
epithelium, the vascular endothelium <strong>and</strong> the liver. In a second<br />
phase, feedback from the other work packages will be used to<br />
produce an improved micr<strong>of</strong>luidics device. In parallel,<br />
development work will be carried out on the cell lines, the NPs<br />
<strong>and</strong> the viability <strong>and</strong> toxicity assays in work package 2. The<br />
chosen cell lines will be optimised for co-culture <strong>of</strong> all cell lines<br />
together under flow conditions. The NPs will be characterised in<br />
detail. Assays for cell viability <strong>and</strong> cytotoxic response will be<br />
tested <strong>and</strong> protocols <strong>and</strong> endpoints will be defined.<br />
In work package 3 the different cell lines from WP2 <strong>and</strong> the<br />
micr<strong>of</strong>luidics device from WP1 will be brought together.<br />
Simultaneous co-culture <strong>of</strong> all the cell lines in the micr<strong>of</strong>luidics<br />
device will be established <strong>and</strong> the whole system will be tested.<br />
Work package 4, in vivo testing <strong>of</strong> NP fate <strong>and</strong> <strong>of</strong> the toxic<br />
effects <strong>of</strong> the NPs in rats, will run for almost the entire duration<br />
<strong>of</strong> the project. The NP preparations optimised in WP2 will be<br />
tested. The rats will be exposed by gavage (ingestion) <strong>and</strong> also<br />
by injection.<br />
In work package 5 the InLiveTox system will be used to<br />
characterise the fate <strong>of</strong> the NPs <strong>and</strong> the toxicological response<br />
they induce in vitro. Finally, the in vivo data will be compared<br />
with results obtained from the in vitro system.<br />
Work package 6, dissemination, exploitation <strong>and</strong> knowledge<br />
transfer, as well as work package 7, project management, will<br />
run for the whole duration <strong>of</strong> the project.<br />
The InLiveTox project, project objectives <strong>and</strong> long-term objectives<br />
As shown in the figure above, the long-term objectives <strong>of</strong> the<br />
project are:<br />
- to ensure the safe development <strong>and</strong> use <strong>of</strong> NPs for<br />
commercial applications<br />
Compendium <strong>of</strong> Projects in the European NanoSafety Cluster 49
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