MicroTotal Pre Analytical Systems (MTPAS): Near-patient Approach to the Preparation of Circulating Biomarkers for Next-Generation Sensing

Increased demand on blood sampling requirements has arisen from prolong lifespan and ageing populations. The use of circulating cell-free nucleic acids (cfNAs) as biomarkers for cancer, non-invasive prenatal testing, organ transplant monitoring and more, has grown in popularity since it is non-invasive (simple blood draw) and easily repeated, allowing the possibility to rapidly establish a diagnosis, a prognosis and even used for theranostic applications. So called "liquid biopsies" and cfDNA analysis could for example allow the fourteen millions of cancer patients diagnosed globally each year to access earlier diagnosis and optimised treatments.
However, despite numerous translational research programs the detection of cfNA is not currently implemented clinically in daily practice. Several reasons have been emerged for this, including (i) the difficulty in controlling the different biological, environmental and logistic parameters from blood sampling to the analysis of biomarkers (ii) the cost of the currently available techniques, which limit accessibility (iii) the turn-around time needed to be useful for patients and clinicians. Current sample preparation solutions are multi-step which can introduce variations and lead to an erroneous diagnosis. Additionally these solutions are time consuming, not amenable to near-patient extraction following blood draw, and require highly trained technicians. The optimisation of the extraction of cell-free circulating markers is key to their translation from the research setting to clinical deployment. The lack of engineering solutions to address the specificities of circulating cell-free nucleic acid extraction, underpins this programme. To meet the requirements of future healthcare industry, the work proposed will integrate novel advanced materials such as electrospun fibres, packaged with on-chip reagents in a microfluidic cartridge to extract cfNAs from blood. Deployed near-patient, this technology will protect the biomarkers from enzymatic degradation and enrich them against the rest of the nucleic acids present in the sample, allowing an unparalleled standardisation and instant preservation of the true disease state until analysis.
The solution proposed involves the use of single-use cartridges, and could generate a significant amount of additional medical waste if implemented. Therefore this programme has a unique sustainable manufacturing component, looking into the use of a naturally-derived plastic (poly-lactic acid) to prototype and manufacture low carbon footprint, disposable, microfluidic cartridges, potential applicable to a large range of point-of-care devices.
The solutions developed in this programme have the potential to significantly reduce the overall cost of sample preparation in the field of circulating biomarkers, as well as increasing the robustness and reliability of a range of biomarkers with direct application in clinical diagnostic and biomarker and drug discovery, in a sustainable fashion. Hand-in-hand with novel sensing solutions, this work has the potential to increase life quality from earlier, quicker diagnosis through optimised treatment and better care management. With the global liquid biopsy market forecasts to reach $4.5 billion by 2020, front-end sample preparation constitutes an important area for the UK economy.

This programme addresses the EPSRC Healthcare Challenge "optimising treatment". The faster extraction of cfNAs will preserve their integrity, preventing alterations and eventually reflecting better on the general health status of patients. Therefore, the miniaturised solution will greatly enhance the specificity, sensitivity and reliability of diagnostics whether in standard mode or POC devices, enabling optimised treatment. Furthermore the programme delivers on the EPSRC Mission and aligns to its strategy through the range of activities, from high quality applied research that meets industrial needs thereby contributing to building leadership and accelerating impact.
My programme is adaptable to a rapidly changing research landscape. The field of genomics is in exponential expansion, and by working with MRC-funded academics focusing on applied genomics, such as Nick Loman, or world leading companies such as Multiplicom-Agilent Technologies, I am best placed to understand and answer the industries immediate and future needs in terms of sample preparation for novel circulating cell-free markers.
Aside from realising academic impacts in my field and beyond, I aim to have a significant impact of the following aspects:
1. Commercial advantage for our industrial UK partner on advanced material, through developing, integrating and demonstration value of material
2. Developing an academic and industrial community around sample preparation to best answer the relevant needs
3. Developing students and staff in multi-disciplinary environments to answer complex real-world problems
4. Creating a pathway for a more sustainable research in micro-engineered medical devices and promoting EPSRC AREA approach
5. Creating technologies that will have tangible impact on patients' quality of life, such as reduced time to diagnosis, optimised treatment and ultimately better outcomes.
To deliver on these impact aims, I have put together a strong pathway to impact, which includes, additionally to normal academic dissemination routes, the following actions:
1. Creation of a clinical and industrial advisory group to monitor progress through-out the programme and advice on a rapidly changing field.
2. To organise proof-of-concept studies with biologists and clinicians to test early prototype outside my laboratory
3. To organise an international workshop on miniaturised sample preparation to build my leadership and galvanise the UK community efforts in this field.
4. To work with end-users and patient groups to disseminate research findings