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

人类矿化牙齿组织是人体中最坚硬的组织，它代表了自然界多层次工程的一个有趣的例子，从原子水平上自然生长的羟基磷灰石晶体在釉和牙本质形成过程中的组装，到它们与有机基质纳米复合材料的结合，再到宏观牙齿的生长，这些牙齿对地球上每个人的生存和福祉起着复杂的长期作用。这是大自然设计的完美典范。然而，以人类龋齿为例，现代富含糖的饮食、形成牙菌斑的细菌和它们产生的酸性环境引起的脱矿作用结合在一起，挫败了复杂的进化过程。在工业化国家，龋齿影响60-90%的学龄儿童和绝大多数成年人，仍然是造成疼痛、痛苦和不安的最持久和最具挑战性的疾病之一。虽然通过水氟化控制这种疾病的进展有据可查，但在大多数情况下，牙医的指示侧重于改变生活方式和口腔卫生的建议，在实践中证明效率有限。根据英国健康和社会保健信息中心（HSCIC）的最新（2016）报告，英国儿童蛀牙率连续四年稳步上升。国家新闻头条（www.bbc.co.uk/news/health-35672775）报道的这些令人震惊的数字使这一研究主题成为人们关注的焦点，这意味着拟议项目的结果可能会产生显著的科学和社会影响。在本提案中，我们希望通过进行系统，协调，多尺度的微观调查，结合数值疾病模型来解决龋齿挑战，以实现更好的诊断，主动干预和治疗龋齿。通过纳米尺度多模态显微镜和建模专家（牛津大学）和牙科研究和教学专家（伯明翰大学）对相同样品应用这种联合的、交叉相关的分析方法，我们将在FIB-SEM和先进的x射线方法所看到的超微结构、化学和成分变化与传统牙科技术可观察到的图案、颜色、信号和迹象之间建立紧密的联系。提案人与全球各地的大学和大型设施研究团体，牙科公司和执业牙医建立了广泛的合作关系。OHI有限公司和专家牙科集团作为合作伙伴的参与，以及德斯坎和钻石光源（DLS）的安全支持将增加和加速影响。这将为新的解释方法和治疗程序铺平一条实用而有效的道路。我们将从纳米级表征到传统牙科技术（x射线摄影和组织学）的见解建立桥梁。我们将建立一个多尺度模型，作为一种预测工具，指导制定最有希望的龋齿治疗策略。该项目的目标与EPSRC医疗技术大挑战的各个方面密切相关，回答了开发未来疗法、控制所需物理干预量、优化治疗以及改变社区健康和护理的主题。与此同时，我们将促进跨领域研究能力的发展，这对实现这些重大挑战至关重要。特别是，本研究将开发采用多模态显微镜的新型成像技术，并利用所获得的见解，通过制定和验证复杂的疾病和治疗数值模型，在计算和数学科学中创造新的方法。这项工作也将有利于传感和分析的先进材料和颠覆性技术领域。

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.