Developing microchips lined with living, human cells, we can overcome the limitations of average patient testing, counteracting the disadvantages associated with primary hepatocytes, cell lines, and animal models. This approach has the potential to totally revolutionise drug development, disease modelling, and personalised, precision medicine across the globe.
Through this technology, we can generate patient-specific, induced pluripotent stem cells, differentiating them into functional and stable liver cells with the potential to reduce attrition by identifying problem compounds early in the discovery process.
This not only results in safer and more effective drugs, but also reduces the cost of drug development.
‘Liver on Chip’ will provide bio-inspired microfluidic environments, allowing the spatiotemporal control of the various chemical and physical culture conditions that are unavailable with other methods. This, in turn, allows for the manufacture of more physiologically relevant drug screening platforms.
This technology can be incredibly beneficial for Pharmaceutical companies as well as contract research organisations involved in drug development. Of course, our technology also has wider applications, including within the drug development R&D process, where it can be utilised for profiling, hit-to-lead, lead optimisation, and pre-clinical R&D.
Multi-species platform for predictive
toxicology and analytics
Hepatotoxicity is the primary cause of drug-related deaths. Drug-Induced liver injury (DILI) remains the most common cited reason for withdrawal of an approved drug from the market. Drug induced liver injury susceptibility depends on age, gender, physiological differences, example, women and children are more susceptible to DILI.
The mechanisms outlining DILI involve three subsequent main steps (See figure):
Drug metabolites or parent drugs can exert initial injury through: (A) direct cell stress, (B) direct mitochondrial inhibition and/or (C) triggering specific immune reactions. Direct cell stress can trigger a wide range of mechanisms, including the depletion of glutathione (GSH). These effects may specifically inhibit other hepatocellular functions, which may cause secondary toxic hepatocyte damage.
Example, Acetaminophen is widely used as an analgesic (painkiller) and antipyretic (anti-fever). It is considered relatively safe at therapeutic doses, however, in overdose it causes acute liver failure.
Mitochondria are cells’s own powerhouse generating 90% of chemical energy. Mitochondria stand in the centre of life and death in hepatotoxicity. Drugs can lead to mitochondrial impairment marked by mitochondrial permeability transition (MPT) (i.e. opening of the ‘MPT pore’ located in the inner mitochondrial membrane) and contribute to liver cell necrosis.
The apoptotic pathway is activated in the presence of sufficient remaining ATP production from the mitochondria. Necrosis occurs if there is no ATP available, which is required for the energy consuming apoptotic pathways.
Innate Immune system plays a role in the toxicity as neutrophils, natural killer cells and inflammatory cytokines have all been implicated in drug induced liver injury. Kupffer cell depletion also exacerbates hepatotoxicity.