Organ on chip technology to evaluate engineered nanomaterial toxicity

项目总结 我们建议将体外毒理学测试现代化，以便于对生物 对工程纳米材料的响应曲线。要确保回复配置文件的高内容评估可以 使用人体相关系统进行测量，我们的平台目前基于芯片上的器官技术 用于药理学和体外疾病模型。我们通过引入以下功能来扩展这些系统的能力 新型曝光芯片，可概括各种曝光途径，并与现有器官芯片接口。 通过暴露芯片将纳米材料注射到底层器官可能会引发暴露途径- 我们的目标是量化的依赖反应。 具体的项目目标包括心脏和呼吸道组织反应谱的定量比较 工程纳米材料直接暴露，穿过组织和内皮屏障，通过组织 工程血管系统，或通过合成皮肤组织。我们主要研究心脏和呼吸道器官模型。 因为它们是成熟的平台，可以提供组织活力、结构和功能的可靠指标，在 对药理学挑战的反应。我们将这些器官系统的能力扩展到纳米材料 通过添加曝光芯片进行毒性测试。为了模拟静脉和局部给药路线， 曝光芯片的连续变化将概括内皮屏障特性并设计 真皮组织的保真度越来越高。 这项拟议的工作建立在我们实验室制造和测试体外芯片器官的专业知识基础上 毒物学平台。我们的团队在这一领域处于领先地位，开发各种器官模型并探索其 用于药物筛选和疾病建模应用的交互作用。我们有丰富的制造经验 模块化器官芯片和拟议的曝光芯片将广泛适用于 最初的重点是心脏和呼吸道系统。我们器官芯片制造的标准化确保了 曝光芯片可以与广泛且不断扩大的武器库或人体器官模型相连接。重要的是，我们 预计这项工作将导致未来的曝光芯片包括更多的递送路线。

PROJECT SUMMARY We propose to modernize in vitro toxicology testing to facilitate comprehensive evaluation of biological response profiles to engineered nanomaterials. To ensure that high-content evaluation of response profiles can be measured using human-relevant systems, our platform is based on organ-on-chip technologies presently used for pharmacology and in vitro disease models. We extend the capability of these systems by introducing novel exposure chips that recapitulate a variety of exposure routes and interface with existing organ chips. Nanomaterials administered through exposure chips to the underlying organs may elicit exposure route- dependent responses that we aim to quantify. Specific project aims include quantitative comparison of cardiac and airway tissue response profiles to engineered nanomaterials administered by direct exposure, through and endothelial barrier, through tissue engineered vasculature, or through a synthetic skin tissue. We focus on cardiac and airway organ models because they are established platforms that provide robust metrics of tissue viability, structure, and function, in response to pharmacological challenges. We extend the capabilities of these organ systems for nanomaterial toxicity testing with the addition of exposure chips. To model intravenous and topical delivery routes, successive variations of the exposure chips will recapitulate endothelial barrier properties and engineered dermal tissues with increasing fidelity. The proposed work builds on our laboratory’s expertise manufacturing and testing organ-on-chip in vitro toxicology platforms. Our team is a leader in this field, developing diverse organ models and exploring their interactions for drug screening and disease modeling applications. We have extensive experience fabricating modular organ chips and the proposed exposure chip will be broadly applicable to organ models beyond the original focus on cardiac and airway systems. Standardization of our organ chip manufacturing ensures that exposure chips can be interfaced with a broad and expanding arsenal or human organ models. Importantly, we expect this work will lead to future exposure chips encompassing an expanding number of delivery routes.