INSPIRE Track1: Computational Design for the Safe Development of High-Aspect-Ration Nanomaterials

该INSPIRE奖的部分资金来自工程局化学生物医学环境和运输部的纳米EHS计划和颗粒和多相过程计划，以及工程局土木、机械和制造创新司的纳米与生物力学计划和材料力学计划。这个拟议的轨道1 INSPIRE项目寻求确定基本的设计规则，以允许安全地开发高深宽比纳米材料(HARN)。Harns是一种一维纤维状或二维片状材料，包括碳纳米管、金属纳米线和石墨烯。简单的等轴测纳米颗粒通常通过化学表面过程启动毒性途径，包括氧化还原反应和可溶性毒物的释放。越来越多的证据表明，Harns通过与靶细胞的几何和纳米机械相互作用来启动毒性途径，从而偏离了这一范式。暴露在长的纳米细纤维或原子薄片中会损害内化和细胞内隔离机制，导致摄取受挫、膜损伤、溶酶体通透性和毒性。这些步骤中的每一个都涉及复杂材料形状与包围细胞或在细胞内形成小泡的生物膜的相互作用。Harns安全设计的关键是了解几何形状如何决定这些生物力学相互作用。这个INSPIRE项目是两个NSF项目的联合成果：CBET环境健康与纳米技术安全(LEAD)和CMMI生物力学与机械生物学。智力优势：项目团队假设对HARNS的生物响应是由几何参数调节的，即碳纳米管的长度和硬度以及石墨烯系列纳米材料的横向尺寸和硬度。采用分子动力学模拟和生物实验验证相结合的方法，对Harns与生物膜和靶细胞的几何和力学相互作用进行了系统的研究。过程颗粒和全原子分子动力学模拟和辅助分析方法将被用来模拟与定义几何形状的Harns相互作用的脂双层，以了解摄取机制、囊泡包装和运输、溶酶体损伤和细胞毒性。平行的实验验证将使肺上皮细胞和鱼鳃细胞暴露在一个独特的Harns面板中，其中包括切割成定义好的长度的多壁碳纳米管，以及横向尺寸不同的几层石墨烯材料。模拟和实验的紧密结合有可能在我们对决定这些新兴纳米产品的纳米毒性的结构-活性关系的基本理解方面实现突破。广泛的影响：新纳米技术的发展应该伴随着理解和管理其对人类健康和环境的风险的平行努力。当今纳米安全领域最重要的两种材料是碳纳米管和石墨烯，这两种材料都是作为高产量产品出现的，对危险评估具有很高的优先级。我们提出的基础科学工作有可能确定Harns的几何特征，这些几何特征是不利健康后果的根本原因，并允许行业重新设计或重新配制材料，以避免这些特征，以提高消费者和工人的安全。该项目还将在材料科学、分子建模和毒理学的界面上对不同的博士生、博士后研究人员和本科生进行交叉培训，并为他们在纳米技术研究或行业中的职业生涯做好准备。最后，调查人员将参与纳米技术商业、安全和监管领域的公共政策讨论，并将帮助转化与新兴纳米管和石墨烯商业部门相关的科学发现。调查人员将继续在涉及商业、法律和监管专业人员的机构和机构赞助的研讨会上，就“通过设计进行预防”的可能性进行全国性讨论。

AbstractCBET - 1344097Hurt, Robert H.This INSPIRE award is partially funded by the Nano EHS Program and the Particulate and Multiphase Processes Program in the Chemical Biomedical Environmental and Transport Division in the Directorate for Engineering and the Nano & Bio Mechanics Program and the Mechanics of Materials Program in the Civil, Mechanical and Manufacturing Innovation Division of the Engineering Directorate. This proposed Track 1 INSPIRE project seeks to identify fundamental design rules to allow the safe development of high-aspect ratio nanomaterials (HARNs). HARNs are a class of one-dimensional fiber-like or two-dimensional sheet-like materials that include carbon nanotubes, metal nanowires, and graphene. Simple isometric nanoparticles often initiate toxicity pathways through chemical surface processes that include redox reactions and release of soluble toxicants. There is increasing evidence that HARNs depart from this paradigm by initiating toxicity pathways through geometric and nanomechanical interactions with target cells. Exposure to long, nano-thinfibers or atomically thin sheets of large lateral dimension can impair internalization and intracellular sequestration mechanisms leading to frustrated uptake, membrane damage, lysosomal permeabilization, and toxicity. Each of these steps involves the interaction of a complex material shape with a biological membrane that surrounds the cell or defines a vesicle within the cell. Key to the safe design of HARNs is to understand how geometry determines these biomechanical interactions. This INSPIRE project is a joint effort of two NSF programs: CBET Environmental Health and Safety of Nanotechnology (lead), and CMMI Biomechanics and Mechanobiology.Intellectual Merit :The project team hypothesizes that the biological response to HARNs is mediated by geometric parameters, namely length and stiffness for carbon nanotubes and lateral dimension and stiffness for graphene-family nanomaterials. A systematic study of the geometric and mechanical interactions of HARNs with biological membranes and target cells is proposed using a combination of molecular dynamics simulations and biological experimental validation on a set of carefully engineered materials of varying length and lateral dimension. Course-grained and all-atom molecular dynamics simulations and supporting analytical methods will be used to model lipid bilayers interacting with HARNs of defined geometries to understand uptake mechanisms, vesicular packaging and trafficking, lysosomal damage, and cytotoxicity. Parallel experimental validation will expose lung epithelial cells and fish gill cells to a unique panel of HARNs that include multi-walled carbon nanotubes cut to well-defined lengths, and few-layer graphene materials of varying lateral dimension. The close integration of modeling and experiment has the potential to achieve breakthroughs in our basic understanding of the structure-activity relations that determine nanotoxicity for these emerging nanoproducts.Broader Impacts:The development of new nanotechnologies should be accompanied by parallel efforts to understand and manage their risks to human health and the environment. Two of the most important materials in the nanosafety field today are carbon nanotubes and graphene, both of which are emerging as high-production-volume products with a high priority for hazard assessment. The basic scientific work we propose has the potential to identify the geometric features of HARNs that are the underlying cause of adverse health outcomes, and allow industry to re-design or re-formulate the materials to avoid those features for improved consumer and worker safety. This project will also cross-train a diverse group of Ph.D. students, post-doctoral researchers and undergraduates at the interface of materials science, molecular modeling, and toxicology, and prepare them for careers in nanotechnology research or industry. Finally the investigators will engage in public policy discussions in the area of nanotechnology business, safety and regulation, and will help translate scientific findings relevant to the emerging nanotube and graphene business sectors. The investigators will continue to engage in national discussions on the potential for "prevention by design" at agencies and agency-sponsored workshops that involve business, legal, and regulatory professionals.