The maintenance of oral health is dependent upon saliva that forms a thin mobile film on soft and hard tissues of the mouth. The salivary film contains an array of proteins that have been demonstrated to perform important functions including lubrication, maintenance of tooth mineralization, protection against soft tissue dehydration and modification of microbial colonization (Nieu Amerongen, AV & Veerman ECI, 2002, Oral. Dis. 8, 12-22). In recent studies by the applicants a method for the objective measurement of mucosal wetness has been validated for use in a clinical setting (Osailan et al. submitted). The protein composition of samples collected in this way has been analysed and the results indicate that mucins are retained on drier surfaces and that the statherin, a surface active salivary protein (Proctor GB, et al, 2005, Biochemical Journal, 389, 111-116) is adsorbed to oral epithelial cells in normal subjects (Pramanik et al., submitted). Statherin was previously shown to act as a boundary lubricant on the enamel surface and is a prominent component of the acquired enamel pellicle (Douglas et al., 1991, Biochem. Biophys. Res. Comm. 180, 91-97). These observations have important implications for the function of saliva as a lubricant and barrier and the alterations that occur in chronic oral dryness. Lubrication is dependent upon the rheological properties of saliva which are closely linked with the content of mucins, however, the details of the mechanism remain relatively poorly understood and the importance of an adsorbed layer of statherin and other proteins, known to have a lubricative effect on solid model surfaces in vitro (Berg et al., 2004, Biofouling 20, 65-70; Lindh L, 2002, Swed Dent J Suppl. 152, 1-57), remains unclear in vivo. An understanding of the latter is crucial to the formulation of oral health products that can effectively alleviate oral dryness. The project will: (1) examine the composition of proteins in saliva and from oral mucosal and tooth surfaces in different subjects with xerostomia, salivary hypofunction or normal controls; (2) develop in vitro models of saliva/ mucosal cell interactions and (3) in vitro measurement of lubrication. Salivas (parotid and whole mouth collected under standardized conditions) will be analysed for protein components (by SDS-PAGE, Western Blotting, ELISAs etc.), ionic components (particularly calcium) by ion-selective electrodes, rheological properties (pendant drop rheometer, Neva meter) and buffering capacity (by acid titration in open and closed systems to account for carbon dioxide absorption/ loss). Salivary proteins on mucosal surfaces (anterior tongue, buccal and hard palate) will be examined by sampling with sterile filter paper strips before and after removal of the fluid film of saliva; the latter will indicate which salivary proteins are adsorbed to surfaces. Salivary protein adsorption to harvested buccal epithelial cells (or to monolayers or full thickness multicell layers of oral epithelial cell lines, e.g. TR146) will also be assessed as a model for salivary protein adsorption to the oral epithelium. Differences between subjects in test groups and matched control groups will be determined. Important proteins identified in the above studies (likely to include statherin and mucins) will be further studied by isolating the proteins from saliva and examining more closely the interaction with oral epithelial cells in vitro. Functional assays using dye-penetration techniques or imaging of mucoadhesive agents such as chitosan will assess how well the models mimic the human pellicles. The dynamics of surface binding to model surfaces in vitro will also be assessed along with the lubricity of adsorbed proteins using in vitro models.

This user-need CDT will equip graduates with the skills needed by the UK formulation industry to manufacture the next generation of formulated products at net zero, addressing the decarbonisation needs for the sector and aligning with this EPSRC priority. Formulated products, including foods, battery electrodes, pharmaceuticals, paints, catalysts, structured ceramics, thin films and coatings, cosmetics, detergents and agrochemicals, are central to UK prosperity (sector size > £95bn GVA in 2021) and Formulation Engineering is concerned with the design and manufacture of these products whose effectiveness is determined by the microstructure of the material. Containing complex soft materials: structured solids, soft solids or structured liquids, whose nano- to micro-scale physical and chemical structures are highly process dependent and critical to product function, their manufacture poses common challenges across different industry sectors. Moving towards Net Zero manufacture thus needs systems thinking underpinned by interdisciplinary understanding of chemistry, processing and materials science pioneered by the CDT for Formulation Engineering at the University of Birmingham over the past twenty years, with a proven delivery of industrial impact evidenced by our partner's letters of support and three Impact Case Studies ranked at 4* in the recent Research Excellence Framework in 2021. A new CDT strategy has been co-created with our industry partners, where we address new user-led research challenges through our theme of Formulation for Net Zero ('FFN0), articulated in two research areas: 'Manufacturing Net Zero (MN0)', and 'Towards 4.0rmulation'. Formulation engineering is not taught in first degree courses, so training is needed to develop the future leaders in this area. This was the industry need that led to the creation of the CDT in Formulation Engineering, based within the School of Chemical Engineering at Birmingham. The CDT leads the field: we won for the University one of the 2011 Diamond Jubilee Queen's Anniversary Prizes, demonstrating the highest national excellence. The UK is a world-leader in Formulation; many multinational formulation companies base research and manufacture in the UK, and the supply of trained graduates, and open innovation research partnerships facilitated by the CDT are critical to their success. The CDT receives significant industry funding (>£650k pa), supported by 31 industry partners including multinationals: P&G, Colgate, Unilever, Diageo, Devro, Fonterra, Samworth Bros., Jacobs Douwe Egberts, Nestle, Pepsico, Mondelez, GSK, AZ, Lonza, Novartis, BMS, BASF, Celanese, Croda, Innospec, Linde/BOC, Origen, Imerys, Johnson Matthey, Rolls-Royce/HTRC, JLR Lucideon and SMEs: Aquapak, CALGAVIN and ITS/StreamSensing. Intra and cross cohort training is central to our strategy, through our taught programme and twice-yearly internal conferences, industry partner-led regional research meetings, student-led technical and soft skills workshops and social events and inter CDT meetings. We have embedded diversity and inclusion into all of our projects and processes, including blind CV recruitment. Since 2018 our cohorts have been > 50% female and >35% BAME. We will co-create training and research partnerships with other CDTs, Catapult Centres, and industry, and train at least 50 EngD and PhD graduates with the skills needed to enhance the UK's leading international position in this critical area. The taught programme delivers a common foundation in formulation engineering, specialist technical training, modules on business, entrepreneurship and soft skills including a course in Responsible Research in Formulation. We have obtained promises of significant industry and University funding, with 67 offers of projects already. EPSRC costs will be 44% of the cash total for the CDT, and ca. £27% of the whole cost when industry in-kind funding is included.

We will train cohorts of graduates from different scientific backgrounds together in a unique interdisciplinary programme that combines physical sciences, computer sciences and biomedicine and breaks down the boundaries between these disciplines. They will apply this interdisciplinary training to develop underpinning new physical science research to address three key UK healthcare challenges: - Rebuilding the ageing and diseased body - Understanding cardiovascular disease - Improving trauma and emergency medicine The research programme will be underpinned by a multi-disciplinary taught programme and enhanced by transferable and project management skills training, as well as Knowledge Transfer and Public Engagement of Science activities. The CDT builds on our four years experience of CDT training of physical scientists at the biomedical interface and harnesses the existing and dynamic research community of excellent physical scientists, distinguished for their ability to and commitment to research at the life science interface, together with a team of leading biomedical scientists and clinicians, with whom there are already established collaborations. This new CDT represents an evolution in our activities and new biomedical foci, while retaining the expertise, ethos and track record of promoting a change in culture at the Physical Science / Biomedicine interface, and of nurturing the next generation of researchers to develop the skills and experience required to explore new physical sciences for biology and healthcare, without the perceived cultural and language barriers. The CDT addresses an identified need from our industrial partners for PhD scientists trained at the interface with biology and medicine, and able to communicate and research across these disciplines, such that they are flexible and innovative workers who can move between projects and indeed disciplines as company priorities evolve and change. This need is reflected in the involvement in and commitment to our bid from our industrial partners. They will co-fund students, offer placements and site-visits, deliver lectures as part of the training and monitor and advise on the training programme. The programme will also benefit from public sector involvement including the Diamond Light Source, local hospitals and Thinktank Science Museum.

Formulation engineering is concerned with the manufacture and use of microstructured materials, whose usefulness depends on their microstructure. For example, the taste, texture and shine of chocolate depends on the cocoa butter being in the right crystal form - when chocolate is heated and cooled its microstructure changes to the unsightly and less edible 'bloomed' form. Formulated products are widespread, and include foods, pharmaceuticals, paints, catalysts, structured ceramics, thin films, cosmetics, detergents and agrochemicals, with a total value of £180 bn per year. In all of these, material formulation and microstructure control the physical and chemical properties that are essential to the product function. The research issues that affect different industry sectors are common: the need is to understand the processing that results in optimal nano- to micro structure and thus product effect. Products are mostly complex soft materials; structured solids, soft solids or structured liquids, with highly process-dependent properties. The CDT fits into Priority Theme 2 of the EPSRC call: Design and Manufacture of Complex Soft Material Products. The vision for the CDT is to be a world-leading provider of research and training addressing the manufacture of formulated products. The UK is internationally-leading in formulation, with many research and manufacturing sites of national and multinational companies, but the subject is interdisciplinary and thus is not taught in many first degree courses. A CDT is thus needed to support this industry sector and to develop future leaders in formation engineering. The existing CDT in Formulation Engineering has received to date > £6.5 million in industry cash, has graduated >75 students and has 46 currently registered. The CDT has led the field; the new National Formulation Centre at CPI was created in 2016, and we work closely with them. The strategy of the new Centre has been co-created with industry: the CDT will develop interdisciplinary research projects in the sustainable manufacture of the next generation of formulated products, with focus in two areas (i) Manufacturing and Manufacturability of New Materials for New Markets 'M4', generating understanding to create sustainable routes to formulated products, and (ii) 'Towards 4.0rmulation': using modern data handling and manufacturing methods ('Industry 4.0') in formulation. We have more than 25 letters from companies offering studentships and >£9 million of support. The research of the Centre will be carried out in collaboration with a range of industry partners: our strategy is to work with companies that are are world-leading in a number of areas; foods (PepsiCo, Mondelez, Unilever), HPC (P+G, Unilever), fine chemicals (Johnson Matthey, Innospec), pharma (AstraZeneca, Bristol Myers Squibb) and aerospace (Rolls-Royce). This structure maximises the synergy possible through working with non-competing groups. We will carry out at least 50 collaborative projects with industry, most of which will be EngD projects in which students are embedded within industrial companies, and return to the University for training courses. This gives excellent training to the students in industrial research; in addition to carrying out a research project of industrial value, students gain experience of industry, present their work at internal and external meetings and receive training in responsible research methods and in the interdisciplinary science and engineering that underpin this critical industry sector.