Precision engineering of complex chemical products used in high-value technology sectors, e.g. pharmaceutical, healthcare and fine-chemical products as well as emergent energy materials, can help achieve superior functionality, control of degradation, and the discovery of novel physical and chemical product properties. Such complex chemical products and devices often incorporate low atomic number ions and molecules as building blocks which, due to their sensitivity to the electron or ion beam, requires a step change in nanoscale chemical and structural imaging, if we are to characterize their detailed microstructure. This grant will advance and enable quantitative, analytical spectroscopy and imaging of these beam-sensitive materials in both their native state and during in-situ dynamic processes at nanometre spatial resolution using a unique set of electron and focused ion-beam microscopy (EM/FIB) instrumentation at Leeds and also externally. This will allow us to identify and create an understanding of unseen performance-limiting structures, defects and interfaces within the soft matter components in such products and devices. In the initial phase of the grant, we will use a combination of three synergistic Research Strategies to achieve our goal for the reliable and accurate characterisation of complex chemical products and devices. These are: (i) the optimisation of sample preparation methodologies; (ii) the development of new electron/ion beam scanning/ shaping strategies; and (iii) the harnessing of new detector technologies for scanning EM/FIB. A set of work packages (WPs) will enable reliable, calibrated methodologies to be developed for the study of the: Structure (WP1), Chemistry (WP2) and Dynamics (WP3) of beam sensitive materials at atomic and molecular spatial resolution in both two and three dimensions, within multiphase environments and with a radical improvement in state-of-the-art chemical sensitivity, whilst simultaneously minimizing beam-induced damage. Collaborations will include: direct partnerships with instrument manufacturers, use of National facilities and secondments to leading international groups with complementary capabilities and expertise, so enabling key advances in nanoscale analytical science for complex chemical products. In the second phase of the grant, these interlinked approaches will, with external user access and direct industrial involvement, be applied to a range of currently unmet challenges in model product/process systems to benchmark potential applications and develop nanoscale models of performance (WP4). Example systems include: (a) the mapping of phase distributions and analysis of interfacial and defect structures in model pharmaceutical formulations, metal-organic framework materials and organic and hybrid optoelectronics; (b) the identification of solution phase precursors, pre-nucleation clusters and hydrates during inorganic/organic crystallization processes; (c) the self-assembly/disassembly of polymeric micelles, micro-gel particles and core-shell particles for drug delivery. In the final workpackage of the grant (WP5), the instrumentation, methods, protocols and expertise so developed will be offered free-at-point-of-use to external academic users and be made available to wider industry to enhance research understanding and impact associated with their specific chemical product systems.

Dental enamel is the hardest mineralised tissue in the body and its complex hierarchical microstructure allows different structural adaptations against the robust challenges in the oral cavity. However, unlike other tissues, enamel lacks the ability to repair or remodel and under conditions of attack by acid produced from bacteria adhering to tooth structure, it loses its integrity and initiates the progression of dental caries, the most widespread dental disease. Despite tremendous efforts to improve oral hygiene and preventive measures by means of fluoridation, more than 2.3 billion adults suffer from caries (Global burden of Disease 2017) and account for massive expenditure as high as £3.4 billion every year (Public health England 2020, NHS England 2014). These distressing details presented in national reports emphasize the prime importance of this research topic and its significant impact on national economy, scientific community, and society in general. To tackle the problem, modern dentistry now aims to curb this dental disease by promoting enamel repair at the initial/incipient stages of caries development to prevent the need for invasive restorative procedures at later stages. In this research proposal we wish to tackle incipient enamel caries by investigating the hierarchical assembly of enamel structure at different length scales (nano- to micro- to macro-) and based on this understanding, develop and refine a new strategy for repair/remineralisation, and ultimately obtain the ability to regenerate enamel with optimal structure and improved properties directly in patients' mouths. By employing a joint interdisciplinary approach involving specialists in dental research at Birmingham and specialists in multimodal microscopy, spectroscopy and modelling at Oxford, we intend to analyse the enamel demineralisation as well as repair by combining conventional dentistry techniques such as clinical visualisation, tactile perception, radiography, laboratory computed tomography etc. with time-resolved 3D structural (hence 4D) evaluation. This will be done at the spatial resolution ranging from atomic crystal lattice to nano, micro-, and macro-scale by advanced microscopic imaging and spectroscopic techniques integrated with microfluidics. The proposers have worldwide associations with research groups across different universities, companies and practicing dentists. Industrial partnership with GlaxoSmithKline and the long established collaborative link with Diamond Light Source (UK synchrotron), ISIS Neutron and Muon source, Tescan and Oxford instruments will provide access to state-of-the-art research methodologies and ensure delivering broadest national and international impact. The project objectives cover (i) identifying and securing supply of representative samples, (ii) observing ultrastructural evolution of enamel during incipient caries demineralisation, (iii) developing and refining minimally invasive remineralisation procedures, and (iv) developing multi-scale mathematical models. This work plan encompasses all themes of EPSRC Healthcare Technologies Grand Challenges ranging from developing future therapies and frontiers of physical intervention to optimising treatment and transforming community health and care. Additionally, the development of macro- and micro-fluidic systems, remineralisation strategies, multi-modal microscopy, and mathematical modelling of enamel structure and the complete disease process shall contribute to the advancement of Cross-Cutting Research Capabilities in areas of advanced materials, novel imaging technologies, and novel computational and mathematical sciences, respectively. The greatest anticipated outcome from the success of this project will be the introduction of new minimally intrusive means of reversing or preventing enamel caries that will be of massive benefit to individuals and the economy, and the society at large.

Human mineralised dental tissues are the hardest tissues in the human body that represent an intriguing example of nature's hierarchical engineering across the scales, from the atomic level assembly of naturally grown hydroxyapatite crystals during amelo- and dentino-genesis to their incorporation into organic matrix nano-composite and the growth into macroscopic teeth that fulfil a complex long-term role crucial to the existence and well-being of every human being on the planet. It is a shining example of nature's design fit for purpose. However, in the instance of human dental caries, the combination of modern sugar-rich diet, plaque-forming bacteria and demineralisation caused by the acidic environment they produce defeats the intricate evolutionary process. In industrialized countries, dental caries affects 60-90% of schoolchildren and the vast majority of adults, remaining one of the most persistent and challenging diseases causing pain, suffering and upset. Although progress in controlling this disease by water fluoridation is well documented, in most cases dentist's instructions focus on recommendations for changes in the lifestyle and oral hygiene, in practice turning out to have limited efficiency. According to the latest (2016) report of the UK's Health and Social Care Information Centre (HSCIC), tooth decay in English children has been steadily rising for four years in a row. These alarming figures reported in national news headlines (www.bbc.co.uk/news/health-35672775) bring this research topic into sharp focus, meaning that the outcomes of the proposed project are likely to make notable scientific and societal impact. In this proposal we wish to tackle the caries challenge by undertaking a systematic, coordinated, multi-scale microscopic investigation, coupled with numerical disease modelling to move towards better diagnosis, and proactive intervention and treatment of caries. By applying this joined-up, cross-correlated analytical approach to the same samples by the specialists in nano-scale multi-modal microscopy and modeling (Oxford) and dental research and teaching (Birmingham), we will establish a tight connection between ultrastructural, chemical and compositional changes seen by FIB-SEM and advanced X-ray methods, and the patterns, colours, signals and signs observable by conventional dentistry techniques. The proposers have extensive partnership links with university and large facility research groups, dental companies and practicing dentists across the globe. Involvement of OHI Ltd. and Specialists Dental Group as partners, and the secured support from Tescan and Diamond Light Source (DLS) will increase and accelerate impact. This will pave a practical and efficient way to new interpretative approaches and treatment routines. We will bridge the insights from nano-scale characterization to conventional dentistry techniques (X-ray radiography and histology). We will build a multi-scale model that will serve as a predictive tool to guide the formulation of the most promising strategies for overcoming caries. The project objectives are closely aligned with all aspects of EPSRC Healthcare Technologies Grand Challenges, answering the topics of developing future therapies, controlling the amount of physical intervention required, optimizing treatment, and transforming community health and care. In parallel, we shall contribute to the advancement of Cross-Cutting Research Capabilities that are essential for delivering these Grand Challenges. In particular, this research will develop novel imaging technologies employing multi-modal microscopy, and use the insights obtained to create novel approaches in computational and mathematical sciences through the formulation and validation of sophisticated numerical models of disease and treatment. The work will also benefit the areas of advanced materials and disruptive technologies for sensing and analysis.

Electro-chemical devices (fuel cells, electrolysers etc) are at the forefront of the drive to a 'net-zero world' with hydrogen as an important energy storage medium and fuel for the application of sustainably derived electricity. Even with the projected development of the energy system towards a largely fossil-fuel free system, CO2 separation will continue to be required for chemical processes. The work proposed builds on the collaboration between the Universities on Manchester, Newcastle and UCL which has flourished over the past five years, to develop more efficient and robust technologies to achieve a carbon negative industrial landscape. The ability to operate fuel cells at higher temperatures without humidification means that the amount of equipment needed and hence cost is reduced. It also means that potentially cheaper catalysts can be used, and the purity of the fuel does not need to be rigorously controlled, all of which leads to cheaper and more efficient systems. The overlap between fuel cells and electrolysers is very significant as an electrolyser is simply a fuel cell in reverse; as such similar problems are manifest. In addition, an exciting electrochemical process for gas separation (CO2 removal) is under development, again with significant overlap in terms of developmental challenges. This proposal builds a team of researchers with complimentary skills to tackle the challenges highlighted. The synergies between the very high-level characterisation expertise to examine the processes taking place in the systems, coupled with the electro-chemical developments which are on-going, mean that development and optimisation can take place quickly with understanding being shared to tackle the overlapping nature of the obstacles to implementation of these vital technologies.

As minimally invasive surgery is being adopted in a wide range of surgical specialties, there is a growing trend in precision surgery, focussing on early malignancies with minimally invasive intervention and greater consideration on patient recovery and quality of life. This requires the development of sophisticated micro-instruments integrated with imaging, sensing, and robotic assistance for micro-surgical tasks. This facilitates management of increasingly small lesions in more remote locations with complex anatomical surroundings. The proposed programme grant seeks to harness different strands of engineering and clinical developments in micro-robotics for precision surgery to establish platform technologies in: 1) micro-fabrication and actuation; 2) micro-manipulation and cooperative robotic control; 3) in vivo microscopic imaging and sensing; 4) intra-operative vision and navigation; and 5) endoluminal platform development. By using endoluminal micro-surgical intervention for gastrointestinal, cardiovascular, lung and breast cancer as the exemplars, we aim to establish a strong technological platform with extensive industrial and wider academic collaboration to support seamless translational research and surgical innovation that are unique internationally.