CAREER: A New Science of Skeletal and Physiological Systems: using integrated approaches to elucidate mineralized tissue properties and behavior

非技术性摘要：这一职业计划寻求整合材料科学、生物学和化学，以阐明磷酸氢在骨溶解中的作用，骨是一种重要的原型和普遍存在的生物材料。这个项目应用多尺度多模型技术来了解磷酸氢在溶解过程中如何影响骨骼结构、成分和功能。骨骼提供结构支持，但它也提供碳酸盐和磷酸氢等缓冲离子，这些离子是调节环境酸度变化所必需的。尽管对酸/碱调节是必不可少的，但骨矿物质的溶解机制仍不清楚。这项研究计划将为操纵和生产复杂的缓冲材料奠定必要的科学基础，这些材料可用于环境修复以及酸中毒等酸/碱疾病的新治疗，提高数百万人的生活质量。此外，调查员的自我效能感教育项目使用自我效能感的心理学概念来整合研究和教育。通过促进进入STEM环境，通过角色建模增加参与，并通过指导调查人员支持学生，将最大限度地发挥通过自我效能建立信心的因素，并促进参与STEM。STEM ACCESS将为本科生、研究生、医学和牙科学生提供在研究人员实验室的积极研究经验。“生物材料”和“舞蹈与物理”课程将进一步让这些学生参与STEM教学活动。女工程师协会将提供一个在K-12和本科生水平上进行角色建模的平台。支架式指导计划将为学生提供成功应对未来职业挑战所需的支持。技术摘要：骨是一种极其复杂的生物材料，具有生物、化学和机械作用。它提供明显的结构支持，但也调节重要的生化和生理过程，包括酸/碱平衡。骨的陶瓷相的溶解是通过释放缓冲离子来调节pH的关键，比如研究得很好的碳酸盐和最被忽视的磷酸氢。由于缺乏跨学科的词汇、知识和技术方法，控制离子释放动力学和程度的骨矿物质溶解机制仍然难以捉摸。PI的职业愿景是将材料科学、生物学和化学整合为一门新的骨骼和生理系统(SAPS)科学，以实现对生理环境与骨骼成分、结构和功能之间相互作用的革命性理解。骨矿是一种钙磷灰石，富含磷酸氢，这表明这种离子起着关键作用。PIS的研究目标是通过建立一个可以应用先进的跨学科材料表征工具和研究方法的实验室，全面阐明骨骼组成之间的关系，特别是在磷酸氢离子含量、结构和生理酸碱调节方面的关系。体外、体外和体内骨骼模型将被用来研究磷酸氢如何影响(1)缓冲反应，(2)晶体结构，以及(3)骨和骨矿物的功能机制，以解开磷酸氢介导的溶解及其与骨结构特性关系和功能的关系。将仿生骨磷灰石和单个骨骼暴露在不同pH值的模拟体液中，以测量骨矿物组成对pH调节的影响以及其离子交换能力。这些模型以及体内生理pH降低的小鼠模型将通过X射线断层扫描和高能X射线衍射(XRD)进行检查，以阐明降低的生理pH和磷酸氢含量对骨的宏观、微观和纳米结构的影响。最后，我们将结合X射线衍射法、数字图像相关法和全骨弯曲等多尺度方法来探讨骨和骨矿物质的力学机制，以研究酸溶解骨矿物质引起的功能变化。从所有三个模型获得的分级数据将被整合到一个统一的模型中，描述酸性环境中骨骼矿物成分、结构和骨功能之间的关系。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Non-technical abstract:This career program seeks to integrate materials science, biology, and chemistry to elucidate the role of hydrogen phosphate on the dissolution of bone, an important prototypical and ubiquitous biomaterial. This program applies multi-scale multi-model techniques to understand how hydrogen phosphate affects bone structure, composition, and function during dissolution. Bone provides structural support, but it also provides buffering ions like carbonate and hydrogen phosphate that are necessary to regulate changes in environmental acidity. Despite being essential for acid/base regulation, the mechanism by which bone mineral is dissolved remains unclear. This research program will establish the scientific foundation necessary to manipulate and produce complex buffering materials that can be used for environmental remediation as well as new treatments of acid/base diseases, like acidosis, improving the quality of life of millions of individuals. In addition, the investigator’s self-efficacy education program uses the psychology concept of self-efficacy to integrate research and education. By facilitating access to STEM environments, increasing participation through role modelling, and supporting students via mentoring the investigator will maximize the factors that build confidence through self-efficacy and promote involvement in STEM. STEM access will involve positive research experiences in the investigator’s lab for undergraduate, graduate, medical and dental students. “Biomaterials” and “Dance & Physics” classes will further engage these students in STEM didactic activities. The Society of Women Engineers will offer a platform for role modeling at K-12 and undergraduate levels. A scaffolded mentoring program will provide students with the support needed to successfully meet future professional challenges.Technical abstract:Bone is an extraordinarily complex biomaterial that fulfills biological, chemical, and mechanical roles. It provides obvious structural support but also regulates important biochemical and physiological processes including acid/base equilibrium. Dissolution of the ceramic phase of bone is essential for pH regulation via release of buffering ions like the well-studied carbonate and the mostly overlooked hydrogen phosphate. The mechanism of bone mineral dissolution, which controls the kinetics and extent of the ionic release, remains elusive due to lack of transdisciplinary vocabulary, knowledge, and technical approaches. The PI’s career vision is to integrate materials science, biology, and chemistry into a new science of skeletal & physiological systems (SaPS) to achieve a revolutionary understanding of the interplay between the physiological environment and bone composition, structure, and function. Bone mineral, a calcium apatite, is rich in hydrogen phosphate, suggesting that this ion plays a key role. The PIs research goal is to fully elucidate the relationship between skeletal composition, especially in terms of hydrogen phosphate ionic content, structure, and physiological acid/base regulation by developing a laboratory that can apply advanced transdisciplinary materials characterization tools and investigative methods. In vitro, ex vivo, and in vivo skeletal models will be used to examine how hydrogen phosphate affects the (1) buffering response, (2) crystal structure, and (3) functional mechanics of bone and bone mineral to unravel hydrogen phosphate--mediated dissolution and its relationship to bone structure property relations and function. Exposure of biomimetic bone apatite and individual bones to simulated body fluid with varying pHs will be employed to measure the effect of bone mineral composition on pH regulation as well as its capacity for ion exchange. These models as well as an in vivo murine model of decreased physiological pH will be examined via X-ray tomography and high-energy X-ray diffraction (XRD) to elucidate the effects of depressed physiological pH and hydrogen phosphate content on the macro-, micro-, and nano-structure of bone. Finally, mechanics of bone and bone mineral will be probed using a multi-scale approach combining XRD, digital image correlation, and whole bone bending to investigate functional changes induced by acid dissolution of bone mineral. Hierarchical data obtained across all three models will be integrated into a unified model describing the relationship between bone mineral composition, structure, and bone functionality in acidic environments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.