Elucidating the pathways for human tooth enamel mineralisation by 4D microscopy and microfluidics

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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.