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.

Riley A et al. (2019). A novel microfluidic device capable of maintaining functional thyroid carcinoma specimens ex vivo provides a new drug screening platform. 19:259. doi: 10.1186/s12885-019-5465-z

Pridgeon CS et al. (2018). Innovative organotypic in vitro models for safety assessment: aligning with regulatory requirements and understanding models of the heart, skin, and liver as paradigms. Archives of Toxicology 92(2):557-69. doi: 10.1007/s00204-018-2152-9

Bower R et al. (2017). Maintenance of head and neck tumor on-chip: gateway to personalized treatment? Future Science 3(2):FSO174. doi: 10.4155/fsoa-2016-0089

Cheah R et al. (2017). Measuring the response of human head and neck squamous cell carcinoma to irradiation in a microfluidic model allowing customized therapy. 51(4):1227-1238. doi: 10.3892/ijo.2017.4118

Greenman J (2017). Looking to the future of organs-on-chip. Future Science 3(2):FSO205. doi: 10.4155/fsoa-2017-0040 

Date K et al. (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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Project grant

Status

Closed

Principal investigator

Professor John Greenman

Institution

University of Hull

Co-Investigator

Mrs Marina Elizabeth Flynn
Professor Stephen Haswell
Dr Leigh Anthony Madden
Dr Anthony Maraveyas

Grant reference number

G1100600/1

Award date

Jan 2012 - Feb 2015

Grant amount

£450,833