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

基本信息

批准号：
7341336
负责人：
Agnes B Kane
金额：
$ 38.1万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/7341336
关键词：
3-Dimensional Adsorption Animal Testing Area Asbestos Bioavailable Biological Biological Assay Biological Availability Biological Models Breathing Caliber Carbon Carbon Nanotubes Cells Cellular Assay Charge Chemicals Chemistry Chronic Classification Complex Computer Systems Development Conflict (Psychology)Cultured Cells Development Devices Dimensions Drug Delivery Systems Elasticity End Point 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 Oxidants 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 Stress Surface Techniques Testing Tissues Toxic effect Toxicology Tube Universities Work base biomaterial compatibility catalyst chemical property commercial application commercialization cost cytokine cytotoxicity design in vivo innovation interstitial lung injury nanofiber nanomaterials nanoscale nanotoxicology novel physical property response size tool

项目摘要

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）由于职业和环境接触纳米材料而对人类健康产生不利影响是一个主要问题，也是对其成功商业化和生物医学应用的潜在威胁。实现其商业潜力需要更好地了解纳米材料与生物系统的相互作用，并制定管理人类健康风险的新策略。制造的碳纳米材料在化学和物理性质、聚集状态和纯度方面变化很大。迫切需要进行毒理学筛查，以识别潜在危险的纳米材料；然而，它们的广泛变异性和独特性质使传统体外和体内毒性测定的解释变得复杂。布朗大学的一个跨学科研究小组，包括一名材料科学家、一名毒理学病理学家和一名分子生物学家，开发了一组新型纳米材料和纳米毒理学检测的创新方法。该模型纳米材料面板将扩展到包括经过严格表征的词汇相关材料特性的选定商业材料。新的合成和表征方法将用于进行系统研究（具体目标 1 和 2），揭示化学（表面状态、金属生物利用度、生物持久性）、结构（尺寸、形状、弹性）和超结构（聚集体尺寸和形状））碳纳米材料毒性的基础。该团队将开发并验证一个独特的平台，用于 3 维培养中的细胞测定，使用肉芽肿的形成、持续的巨噬细胞激活和纤维化作为病理终点（具体目标 3）。该平台将结合纳米材料的暴露后表征与非细胞测定并行，以评估模拟细胞内环境中的生物持久性和聚集状态（具体目标 4）。将开发细胞因子表达谱来预测碳纳米材料相对于标准参考材料的毒性（具体目标 5）。预计这种经过验证的毒理学筛选试验将以较低的成本和减轻动物试验的负担提供慢性啮齿动物吸入试验的替代方案。确定导致细胞毒性的纳米材料的特定化学和物理特性将有助于开发制造方法和后处理步骤，以消除内在毒性。