Particle Filtration and Accumulation by Solute-driven Transport (FAST) for bio-analysis in microfluidic devices

The outcomes of many health interventions critically depend on the ability to identify the disease in a timely manner so the most appropriate therapy can be chosen promptly. Consequently, there is an immediate and growing need to develop healthcare technologies for rapid and accurate detection of bio-markers, associated with specific diseases, and/or disease causative agents, such as pathogenic microorganisms. Microfluidics and lab-on-a-chip technology offer a huge potential for the development of next generation fast and ultra-sensitive bio-analytical devices for diagnostic and therapeutic applications.

Particle handling operations - including separation, filtration, concentration, trapping and sorting - are ubiquitous in microfluidic diagnostic technologies and can ultimately dictate the speed, accuracy and selectivity of testing devices. An ideal particle handling technique would be fast (high-throughput), selective (i.e. targeting only the particles of interest), easy to integrate into a multifunctional microfluidic device and, most importantly, not reliant on the use of external fields. This proposal aims to introduce an innovative particle manipulation technique to address all these requirements. This research will also demonstrate the proof-of-concept for using this technique to develop fast and sensitive diagnostic testing devices.

Rapid filtration, trapping and accumulation of target particles within the cavities of micro-structured surfaces will be achieved in continuous flow settings by harvesting the chemical energy associated with salt contrast generated by parallel multi-component flows. The mechanisms governing the particle dynamics will be investigated through a combination of experimental and numerical techniques. The dependence of trapping and concentration efficiency on particle properties (especially size and surface chemistry) will be elucidated. The output of this study will be an optimally-designed microfluidic platform, through which two in-vitro diagnostic devices will be developed. One device will enable the rapid filtration of cell-like particles (e.g. liposomes) based on their lipid membrane composition which is an important indicator of a cell's state of health. This assay will offer new opportunities for early detection of drug induced cell death and rapid drug pharmacokinetics screening. Another device will enable the fast and ultrasensitive detection of a biomarker indicative of pathological conditions, including atherosclerosis, pancreatitis and some forms of cancers. Synthetic bio-compatible particles will be incubated in a sample solution where the specific interaction with the disease biomarkers will cause i) the fluorescent signal emission from the particle and ii) a change in particle surface chemistry. The latter effect is intended to enable the conversion of the chemical energy - stored in the form of salt contrast - into particle motion. As a result, the biomarker-activated fluorescent particles will be rapidly trapped and accumulated within target regions of the device whereas the non-fluorescent particles will remain unaffected by the presence of the salt. This will enable a massive signal amplification for the diagnostic assay and, consequently, a fast and accurate detection of biomarker concentration in the analysed sample.

In summary, this research will lay the foundation for the development of a new family of low-cost, portable bio-analytical devices based on particle filtration and accumulation by solute-driven transport (FAST) for diagnostic and therapeutic applications. These innovative and highly-sensitive diagnostic tools will enable clinicians to perform rapid and accurate diagnosis and, hence, make timely and informed clinical treatment decisions which are more likely to lead to successful health outcomes.

The project aligns with the EPSRC's prosperity outcomes in Health and Productivity and has potential for significant impacts at different levels. Many chronic disorders, including cardiovascular and metabolic diseases, dementia and cancers, may be asymptomatic until the latter stages of the disease, at which point the chances of successful treatments are reduced and the cost of health intervention increased. It is predicted that in UK every year around 50,000 individuals receive a late diagnosis of cancer, this resulting in ca. £210 million in extra cost for the NHS [Birtwistle et al, Saving lives, averting costs. Cancer Res. UK, 2014]. These numbers increase rapidly when other forms of asymptomatic diseases are accounted for.

Societal and economic impact will be realised through improved diagnosis and treatment opportunities offered by the development of a new paradigm for bioanalysis in microfluidic systems. By establishing a new particle manipulation strategy and introducing a proof-of-principle microfluidic platform for bio-analysis, this research will support the development, over the next 10-15 years, of novel low-cost bio-analytical microsystems with better sensitivity, shorter analysis time and higher throughput. Providing clinicians with such new bio-analytical tools will enable them to make more accurate diagnoses at earlier stages in the disease's course even in out-of-hospital settings (e.g. GP's surgery or patient's home). Consequently, patients - especially elderly individuals, those with asymptomatic and/or chronic diseases and/or limited mobility - will benefit from earlier diagnoses, improved treatment and, hence, higher chances of better health outcomes. Project outcomes and follow-up research activities, detailed in the "Pathways to Impact", will contribute towards the UK life science sector's ambition to radically transform the paradigm of healthcare delivery over the next two decades by shifting from a healthcare system providing costly treatments in hospitals for late-stage patients to a more economically sustainable system based on low-cost point-of-need early diagnoses, prevention and rapid intervention.

This research has further potential for economic impact by contributing to innovation in UK industry leading to commercial realisation of innovative bio-analytical and in-vitro diagnostics technologies - a market in the UK worth ca. £2.6 billion in 2014 and expected to reach £3.4 billion in 2020. End users of this research include enterprises in the UK focusing on manufacture of portable microfluidic systems for applications in chemistry, biology and medicine. Providing industry manufacturers with innovative methods for particle manipulation and bio-analysis will offer tremendous opportunities for design and commercialisation of a new family of microfluidic system products for bio-analysis, diagnostics, drug screening and drug delivery. This will enrich the product portfolio of these end users, enhance their global competitiveness and allow them to exploit new and rapidly expanding markets, such as those emerging from a growing population of elderly individuals with complex health needs. Examples of innovative products may include point-of-need diagnostic chips, microfluidic systems for cell filtration/analysis and microdevices for drug-cell interaction studies and drug development.

Finally, it is well recognised that interdisciplinary research has a critical role in bridging the gap between industry and academia - especially in the field of microfluidics and healthcare technologies. By bringing together project partners and advisors with expertise ranging from colloid and interface science to biochemistry, from the physics of liquids to healthcare and diagnostics, research staff at PhD and post-doctoral levels will be trained in a highly interdisciplinary environment and equipped with technical and transferable skills required to become future research leaders in UK industry and academia.