Replacement of animal models for tumour biology with a multifunctional microfluidic-based approach

The aim of the project is to design and optimise a microfluidic device in which small biopsies of human tissue (malignant and normal) can be maintained in a biomimetic-like environment. It is proposed that these devices will be used both by pharmaceutical companies to reduce and replace drug screening and by clinicians as tools for personalising a therapeutic strategy. It is planned to investigate the pro-coagulant changes that occur in many cancers as the process is a major clinical problem and provides an ideal setting to demonstrate the widespread applicability and potential of the microfluidics platform. To investigate the reasons why a venous thromboembolism is commonly associated with tumours, tissue biopsies (2-3m3) will be maintained in a small chamber on the chip (approximately 20 ƒÝl in volume) for up to 8 days with media, or media plus drugs at clinically-relevant doses, perfusing the tissue. A major benefit of the microfluidic approach is that not only can drug combinations be tested, but also the most effective sequence of administering drugs can be rationally determined. This type of analysis is not possible in animal models as the one end point is almost always death. Additionally, normal tissue will be tested in the devices allowing side effects such as non-specific toxicity to be identified. It is proposed to establish three distinct analysis modules measuring different facets of the clotting process: coagulation, using viscosity and direct fluorescence imaging; MP release, by dual colour flow cytometry; and gene transcription using hybridisation and fluorescence detection. The modules can be used in parallel due to a switch mechanism on the chip and on multiple occasions, thus a response can be monitored over time. These integrated devices will provide data on the responses that have far greater relevance to the in vivo setting than any animal model. A key aim of the proposal is to demonstrate the robustness of the microfluidic device and compatibility of the data generated on-chip with conventional cell assays. Having established the operating parameters of the device it is proposed to test a cohort of ovarian tumour samples using a standardised chemotherapy regimen (paclitaxel plus carboplatin) alone, and in combination with a currently used VTE treatment. The results of this microfluidic trial will be correlated with the clinical outcome. Finally, a small group of tumours will be used to establish the optimal drug concentrations and dosing sequence for each tumour, i.e. a personalised treatment.

Date K, Hall J, Greenman J, Maraveyas A, Madden LA (2013). Tumour and microparticle tissue factor expression and cancer thrombosis. Thromb Res 131(2): 109-15. doi: 10.1016/j.thromres.2012.11.013

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Jan 2012 - Feb 2015

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