Chemical, Structural, and Superstructural Determinants of Nanocarbon Toxicity

纳米碳毒性的化学、结构和上层结构决定因素

• 批准号: 7625054
• 负责人: Agnes B Kane
• 金额: $ 37.24万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625054
• 关键词: 3-Dimensional; Adsorption; Animal Testing; Area; Asbestos; Bioavailable; Biological; Biological Assay; Biological Availability; Biological Models; Breathing; Caliber; Carbon; Carbon Nanotubes; Cell Culture Techniques; Cells; Cellular Assay; Charge; Chemicals; Chemistry; Chronic; Classification; Complex; Computer Systems Development; Conflict (Psychology); Development; Devices; Dimensions; Drug Delivery Systems; Elasticity; Environment; Environmental Exposure; Exposure to; Fibrosis; Fullerenes; Granuloma; Hand; Health; Housing; Human; Hydrophobicity; In Vitro; Inflammation; Injury; Interdisciplinary Study; Length; Lung; Macrophage Activation; Mediator of activation protein; Metals; Methods; Modeling; Molecular; Molecular Profiling; Morphology; Movement; Nanotechnology; Nanotubes; Neurons; Occupational; Osteoblasts; Oxidation-Reduction; Pathologic; Pathologist; Population; Price; Process; Production; Property; Reaction; Reference Standards; Relative (related person); Risk; Rodent; Role; Scientist; Screening procedure; Sepharose; Shapes; Simulate; Site-Directed Mutagenesis; Surface; Techniques; Testing; Tissues; Toxic effect; Toxicology; Tube; Universities; Work; base; biological systems; biomaterial compatibility; catalyst; chemical property; commercial application; commercialization; cost; cytokine; cytotoxicity; design; in vivo; innovation; interstitial; lung injury; nanofiber; nanomaterials; nanoscale; nanotoxicology; novel; oxidant stress; physical property; response; tool

DESCRIPTION (provided by applicant) Adverse human health effects due to occupational and environmental exposure to nanomaterials are a major concern and a potential threat to their successful commercialization and biomedical applications. Realization of their commercial potential will require a better understanding of the interactions of nanomaterials with biological systems and the development of new strategies to manage human health risk. Manufactured carbon nanomaterials are highly variable with respect to chemical and physical properties, state of aggregation, and purity. Toxicological screening is urgently needed to identify potentially hazardous nanomaterials; however, their wide variability and unique properties complicate interpretation of traditional in vitro and in vivo toxicity assays. An interdisciplinary research team at Brown University including a materials scientist, a toxicologic pathologist, and a molecular biologist has developed a panel of novel nanomaterials and innovative approaches for nanotoxicology assays. This panel of model nanomaterials will be expanded to include selected commercial materials subjected to rigorous characterization of lexicologically relevant materials properties. Novel synthesis and characterization methods will be used to carry out systematic studies (Specific Aims 1 and 2) that reveal the chemical (surface state, metals bioavailability, biopersistence), structural (size, shape, elasticity), and superstructural (aggregate size and shape) basis of carbon nanomaterial toxicity. This team will develop and validate a unique platform for cellular assays in 3- dimensional culture using formation of granulomas, persistent macrophage activation, and fibrosis as pathologic endpoints (Specific Aim 3). This platform will incorporate post-exposure characterization of nanomaterials in parallel with an acellular assay to assess biopersistence and aggregation state in simulated intracellular environments (Specific Aim 4). A cytokine expression profile will be developed to predict toxicity of carbon nanomaterials relative to standard reference materials (Specific Aim 5). It is anticipated that this validated toxicologic screening assay will provide an alternative to chronic rodent inhalation assays at lower cost and reduced burden of animal testing. Identification of specific chemical and physical properties of nanomaterials responsible for cellular toxicity will enable development of manufacturing methods and post processing steps to eliminate intrinsic toxicity.

描述（由申请人提供） 由于职业和环境暴露于纳米材料而引起的不利人类健康影响是对其成功商业化和生物医学应用的主要问题，并且潜在的威胁。实现其商业潜力将需要更好地理解纳米材料与生物系统的相互作用，以及制定管理人类健康风险的新策略。对于化学和物理性质，聚集状态和纯度，制造的碳纳米材料是高度可变的。迫切需要进行毒理学筛查，以鉴定潜在的危险纳米材料。但是，它们的广泛可变性和独特的特性使人们对传统体外和体内毒性测定法的解释变得复杂。布朗大学的一个跨学科研究团队，包括材料科学家，毒理学病理学家和分子生物学家，已经开发了一组新型的纳米材料和纳米毒理学测定方法的创新方法。该模型纳米材料面板将扩展，包括经过严格表征词典相关材料特性的选定商业材料。新型的合成和表征方法将用于进行系统研究（具体目的1和2），该研究揭示了化学（表面状态，金属生物利用度，生物抗性），结构性（大小，形状，弹性）和上层结构（骨料和形状）的结构（尺寸，形状，弹性和形状）。该团队将使用颗粒瘤，持续性巨噬细胞激活和纤维化作为病理终点的形成，开发并验证一个在3维培养中的细胞测定平台（特定目标3）。该平台将与纳米材料的暴露后表征与链细胞测定法并联，以评估模拟细胞内环境中的生物存在和聚集状态（特定目标4）。将开发细胞因子表达谱，以预测相对于标准参考材料的碳纳米材料的毒性（特定目标5）。预计该经过验证的毒理学筛查测定法将以较低的成本和减轻动物测试负担的替代品提供慢性啮齿动物吸入测定法。识别负责细胞毒性的纳米材料的特定化学和物理性质将使制造方法和后加工步骤的发展以消除内在毒性。