Colorectal Cancer (CRC) is the third most common cancer in the UK, with approximately 32,300 new cases diagnosed and 14,000 deaths in England and Wales each year. Occurrence of colorectal cancer is strongly related to age, with 83% of cases arising in people older than 60 years. It is anticipated that as our elderly population increases, CRC will increase in prevalence (National Institute for Clinical Excellence, www.nice.org.uk). This raises important questions relating to treatment in elderly patients balanced with quality-of-life and health economics considerations. The challenge to nanotechnology and engineering is to deliver cost-effective, less invasive treatments with fewer side-effects and potential benefits for quality of life in patients. This is particularly important in CRC at the present time as the NHS bowel-screening programme is rolled out for all individuals aged 60 to 69. This raises important issues for rapid, accurate, and acceptable, safe and cost-effective investigation and treatment of older symptomatic patients. Ultrasound has a clear and growing role in modern medicine and there is increasing demand for the introduction of ultrasound contrast agents such as microbubbles (MBs). These MBs are typically less than one hundredth of a millimetre in size, so that they can pass through the vasculature, and lead to imaging enhancements by scattering of the ultrasound signal. So-called third generation MBs will not only perform functional imaging with greatly enhanced sensitivity and specificity but will also carry therapeutic payloads for treatment or gene therapy. These will most likely be released by destroying the bubbles at the targeted site and their effect enhanced further by sonoporation (sound induced rupture of the cell walls to allow drugs in). Although the focus of our proposal is therapeutic delivery for cancer treatment, the basic technologies for MB development and ultrasound technology are equally applicable to other conditions e.g. cardiovascular and musculoskeletal disease where there is an unmet clinical need, particularly in ageing populations. As such this is a generic technology development relevant to different diseases.Our programme of research addresses several key issues central for the successful development of these 3rd Generation MBs. Firstly, we propose to develop a machine, based on microfluidics, for the creation of MBs of uniform size (necessary for human application). This instrument will also allow us to put suitable coatings on the MBs to target them specifically at cancerous cells. Secondly, we will develop novel coatings to allow control over the way bubbles respond to ultrasound signals. We will then add payloads of the required drug to be delivered onto the micro-bubble surface. At the same time we will develop novel methods of generating ultrasound signals which can be used to selectively destroy the MBs and simultaneously create holes in the cells to which the drugs should be delivered. A necessary part of such a programme of research is the full testing and evaluation of the MBs developed for targeted therapy of CRC using a combination models. Firstly, against cancer cells grown in test tubes and secondly, against mice infected with the relevant cancer. At the conclusion of our research project we will have enhanced our understanding of how MB and ultrasound technologies can be combined to yield new routes for therapeutic delivery/gene therapy. This will provide a platform to launch the next stage of research, required before such an approach could be used clinically.

Infectious diseases remain a primary cause of morbidity and mortality in many Low and Middle Income Countries, which suffer from limited health infrastructure, poverty and political insecurity, increasing the transmission of a broad range of human and animal infectious diseases. Our vision for our network is that our new mobile phone enabled low cost DNA sensor technology, based upon using paper microfluidics, will bring both health and economic benefit to East Africa, including both Uganda and Tanzania, as well as other countries in Sub-Saharan Africa in future. The new diagnostic technology will I particular strengthen laboratory diagnostic capacity, which is a main focus for cooperation according to the WHO Cooperation Strategy for Uganda for example. We have already demonstrated the connectivity through apps and the cloud, accessing secure data storage and artificial intelligence/machine learning decision support tools to help healthcare providers make the correct diagnosis for multiple infectious diseases from the same sample. We now predict, that by using this technology, end users will be enabled to perform infectious disease diagnosis in humans and livestock using different samples, including water, milk and blood. In doing so we will be able to determine, quantitively, transmission pathways between animals and humans (whether this be through shared water sources or unpasteurised milk) - thereby helping address the following Sustainable Development Goals, SDGs, 2, 3, 6 and 15. This will provide healthcare technologists and epidemiologists better understanding of the impact of these diseases in veterinary care, as well as in human infection in the specific environment in Uganda and Tanzania - with resulting economic and health benefits, reducing poverty - address SDG 1. We aim to use this activity as a case study to both exemplify the broader impact of mobile diagnostics on digital health platforms, to inform Governments, NGOs, Charities, Universities, Industry as well patients and the public more generally, as well as to build a wide network of stakeholders in mobile diagnostics platforms to identify and overcome barriers to deployment of digital health solutions in Uganda and Tanzania, and beyond. Our network will address one of the major health challenges highlighted by both Tanzania and Uganda, through the development of low-cost quantitative diagnostics and screening tools, enabling timely investigations of the factors contributing to the persistence of infectious diseases. In addition to delivering impact on increased health and economic benefits, the outcomes from the network will significantly decrease the impact of infectious diseases on women, who currently have a disproportionate burden. They not only provide the main support for young families, including responsibility around caring and cooking for children, and providing education, but also provide 80% of the labour for rural agricultural activities. Illness in women leads to a direct loss in the family's income, and prevention of disease can subsequently provide additional economic benefit (SDG 3, 5 & 10). Similarly, if children are ill, they are often taken out from school, again resulting in a loss of income as well as missed education opportunities (SDG 4). In the case of human disease, as of 2017, malaria was the 3rd leading cause of death in both Uganda and Tanzania. By enabling delivery and connectivity of diagnosis in rural communities, using digital health, our network will allow local communities and governments to both increase the efficiency of treatment (through increased decision support) as well as build and implement surveillance strategies to prevent epidemics and re-emergence of diseases.

The aquaculture industry in South Asia, and in particular shrimp farming in India, has been growing rapidly and now has significant potential to alleviate poverty within low-income regions and communities. In these settings, farms are often small (90% of the shrimp farmers in India use <2ha of land) and are run by poor families. However, they can generate benefits across a large portion of the local population, through improved employment, increased income (from jobs associated with the industry and its supply-chain, as well as through export for example). These benefits can flow to wider community, locally, alleviating poverty. However, these benefits are generally not realised, as the production from these farms is not sustainable, mainly due to the high frequency and impact of outbreaks of infectious diseases, which destroy crops and yield slow growth, resulting in significant impact on the farms themselves but also on the wider communities and economy. At a national level, this translates into ca. 50,000 Metric Tonne (MT) losses (ca. £1B) and loss of employment of 2.15 million man days per annum. In this project, we will translate a novel, low-cost, battery-powered handheld platform for the early, multiplexed detection of pathogens at the farm or hatchery, to empower local farmers and communities to control and reduce the occurrence and impact of disease outbreaks. We will work with our partners Ananda (a well-established, seafood company, based in the hub of Indian shrimp farming in Andhra Pradesh), ICAR-Central Institute of Fisheries Technology, (in Cochin), Mologic (a provider of rapid diagnostic tests), Epigem (a manufacturer of low-cost devices) and the Centre for Environment, Fisheries and Aquaculture Sciences Cefas (aworld leader in marine science and technology in the UK), to design, validate and deploy the tests in the field in India. The current diagnostic tests, which are used in India and elsewhere in South Asia, are based on nucleic acid-based detection, which takes a few hours to perform, in a well-resourced laboratory, using sophisticated equipment. This has two major consequences: (i) the tests are not available to poor farmers (the majority), either at all, or at a frequency that would allow to monitor the production reliably and detect potential outbreaks timely; and (ii) when they are carried out (e.g. at Ananda), they require the samples to be transported to where expertise is available, which leads to significant delays in results (often many days). These delays can result in mis-timed inaction (and the potential to lose the crop), emergency harvesting (leading to decreased economic output), or, in some cases, the mis-use of antibiotic or chemical treatment, which has the potential to increase drug resistance and contaminate the environment. In this project, we will deliver a step-change in the farmer's abilty to reduce the impact of production-based losses and the burden associated with ineffective treatments. The platform relies upon the enrichment of pathogens from shrimp tissue using a combination of paper-based filtration and magnetic beads, onto a paper-based biosensor. By folding the paper, in a process akin to origami, the genetic material of the pathogens is purified and distributed into specific areas, where nucleic acids are amplified. This amplification (performed using a small hand-held heater, with low power at around 60oC, but which could also be performed in a thermos flask) is then detected using either direct visualisation of a colour change, as in pregnancy tests, or using a mobile phone to quantify the response, within 45min. By developing and deploying a low-cost, point-of-use detection device, we will empower small-scale farmers with the ability to identify pathogens early, thus allowing them to take remedial actions as well as liaise with the community to ensure outbreaks are contained.

This proposal is a Platform Grant renewal. Our previous grant allowed us to develop the key characterisation facilities and enabled us to understand fully the materials that were the study of the grant. These materials were low loss microwave dielectrics, ferroelectric materials and thin films of these materials. The Platform renewal will build upon some remarkable discoveries that the team, including the key PDRAs, has made over the last 4 years and centre around functional materials for devices operating from microwave to millimetre wave or from MHz to THz. First it is important to explain the Materials Science progress that forms the underpinning technologies that will enable us to use the Platform grant to build new devices. At the heart of microwave devices are resonators that require low dielectric loss or very high Q factor and the target is to aim for very high Q dielectrics. Our previous Platform grant and indeed prior support from EPSRC allowed us to discover very low loss, high Q materials. This culminated in two significant discoveries. 1 First we were able to use low loss resonators as sensors for liquid sensing 2 Second, we demonstrated that by using a very high Q resonator we could achieve maser action at room temperature and in Earth's field - published in Nature 2012. This platform grant will enable us to build upon these discoveries. 1) Advanced Characterisation: In the first theme the aim will be to carry out a series of qualifying experiments to determine the best possible conditions and materials for sensing over the wide range of frequencies available to us (Hz to THz) 2) Microwave and mm wave sensors: The third theme takes the science to application. We will use the resonators for analysis of ions, biomolecules, proteins and cells. The sensitivity of the resonators allows nanolitre quantities to be analyzed very rapidly for possible cancer cell detection in blood and bacteria in water. 3) "UMPF" and "HEP" Cavities: In the second theme we aim to make UMPF (Ultrahigh Magnetic Purcell Factor) and "HEP" (High Electric Purcell) cavities. These are small resonant cavities with a very high Q given the very small mode volume and success here will enable us to improve electron paramagnetic sensing dramatically and enable single cell detection. Success in these new themes for the Platform would represent a remarkable step-change in technology.

The research, which will be carried out in the School of Engineering at the University of Glasgow, will underpin a completely new paradigm in the handling of liquids. It involves the control of the mechanical interactions between fluids and microfabricated structures, with acoustic waves. Notwithstanding its potential impact on a wide range of areas (e.g. physics and chemistry), my focus in this Fellowship will be in enabling advanced diagnostics both in remote areas in developing countries and in the developed world, by integrating complex biological sample processing on low cost portable devices. Acoustic waves carry a mechanical energy that has been successfully used to actuate a wide range of liquid functions. In particular, Surface Acoustic Waves (SAW) propagated on piezoelectric surfaces, using transducers commonly found in electronics, can refract in a liquid, leading to recirculation flows. I have pioneered and enhanced a technique to control SAW and their interactions with the liquid and particles, enabling more complex manipulations. The new platform is based on micromanufactured, disposable phononic lattices, that scatter or reflect the acoustic waves in a frequency dependent manner. These structures shape the acoustic waves, in a manner analogous to that of holograms shaping light. The structures rely on mechanical contrast when holograms are based on refractive index. Geometric aspects of the hologram's design provide colours of different frequencies; here, the phononic lattice geometry determines the frequency at which the sound is scattered. The different frequencies of ultrasound interact with different phononic structures to give different functions, providing a "tool-box" of different diagnostic processes (sample processing, cell separation, detection), which, when combined, form a fluidic circuit, a complete diagnostic assay. Contrary to the established microfluidic systems used in point-of-care devices, which rely on flow through channels to carry out different functions at different positions within the channels, I will design, fabricate, characterise and use new phononic lattices to combine different functions in the frequency domain, on a stationary sample. Others involved in the research include Professor Miles Padgett (School of Physics), Professor Andy Waters (Welcome Centre for Molecular Parasitology), Dr Andrew Winters (Consultant in Sexual Health & HIV Medicine and Joint Clinical Director at The Sandyford Clinic, NHS Greater Glasgow and Clyde) and Dr Mhairi Copland (Paul O'Gorman Leukaemia Research Centre and the Beatson Cancer Research. My research will have three potential outcomes in diagnostics and sensing, namely the development of new Microsystems technologies for: 1. Drug resistant malaria diagnostics. I will develop phononic geometries to carry out a complete nucleic acid based test, including sample preparation, amplification, and detection in whole blood. These will be fabricated in low cost materials (e.g. glass, composites) and could transform malaria diagnostics in the Developing World. 2. Multiplexed detection of a panel of sexually transmitted diseases, working with the NHS. The ability to perform complex sample preparation has the potential to integrate multiplexed analysis in an expert system, where instead of a diagnostic test centered around a pathogen, the test has the capability to analyse a set of symptoms, a decisive shift in diagnostics. 3. Stratification of leukemia cells' aggressiveness. I will explore how the combination of the cells mechanical information probed using acoustics, and coupled with electrical information on cell membranes, could enable a multidimensional analysis of cells. This research will have the potential to create devices to carry out diagnostics anywhere.