Tackling human dental caries by multi-modal correlative microscopy and multi-physics modelling

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.

In terms of the economic and societal impact, the principal project outcomes will have far-reaching implications in health and lifestyle, social policy and commerce, leading to drastic improvements in the quality of life and state of health, and contributing to personal happiness of many people. UK enjoys a leading position in many aspects of medical research, with therapies and approaches developed here successfully adopted across the globe. Each new major advance taken up by UK practitioners and health technology companies gets progressively accepted and used in Singapore Australia, US, Japan, and many other countries. Leading new treatment development brings tangible economic benefits to UK. Outcomes of this project will change the formulation of dental rinses and toothpastes (global market of ~$12.5bn, topping dental implants market of ~$8bn). Also affected will be the dental consumables market including filling restorative materials and adhesives approaches ~$20bn worldwide. Overall, long-term emphasis shift will be from routine caries treatment to prosthodontics and functional restoration procedures.
For knowledge impact, the integrative paradigm of tight combination of cutting edge characterisation techniques with advanced multi-physics modelling will elucidate the course of disease and treatment across the scales, and deliver crucial understanding and ability to control the disease in a targeted and bespoke fashion. Cross-fertilisation between disciplines of multi-modal microscopy and dental therapy will attract more researchers with physical sciences background to the study of biological tissues and treatments. Advancing novel approaches to structural and compositional analysis of human tissues will be used to study other mineralised tissues, such as bone; Advances in microscopy (X-ray) techniques will benefit major partners and collaborators active in the field, such as Tescan and Oxford Instruments, DLS and RCaH, and smaller entities (Deben Research, Alemnis and WITec). These connections will ensure that progress achieved in experimental technique development will become embodied in publicly and commercially available setups and instruments, benefitting numerous researchers in the field; Dissemination of outcomes to industrial and academic researchers of modelling activities will enhance the general level of awareness and understanding in the field, and become available in the form of software packages, such as Matlab, Mathematica, and Abaqus.
For translation from research into practice, it will put new insights from nano-scale imaging into the context of evidence from more widespread methods of oral histology, radiography and spectral imaging, making them directly accessible to practitioners such as project partners: Specialists Dental Group, Singapore, Oral Health Innovation Ltd in Birmingham, UK. In addition, the links with dental supplies companies, such as Ivoclar Vivadent, GSK Oral Healthcare will be maintained and developed. Patent applications will be made through Oxford and Birmingham university IPR companies.
For human capital, this project will educate post-doctoral researchers in a complex, multi-faceted, multi-disciplinary project. Dr Tan Sui already fulfils the role of manager for the group electron microscopy (MBLEM) and X-ray diffraction and imaging (HEX) facilities. This project will contribute to her experience, and provide an excellent foundation for her to seek a permanent post in academia. Final year undergraduate students of BMedSc (Birm) and MEng (Ox) will benefit from being exposed to cutting edge research challenges, and may continue towards doctoral study. We will welcome visiting students from collaborating institutions across Europe.
Broader dissemination of our scientific results will take place through specialised workshops and active publication in periodicals such as Nature Communications, Acta Biomaterialia, J Dental Research, and Materials & Design that PI and RCI co-edit.