PFI-TT: A novel human developmental toxicity assay platform using microfluidics

PFI-TT：一种使用微流体的新型人类发育毒性测定平台

• 批准号: 2213845
• 负责人: Jianping Fu
• 金额: $ 25万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2213845&HistoricalAwards=false
• 关键词: PFI; TT; novel; human; developmental

The broader impact/commercial potential of this Partnerships for Innovation - Technology Translation (PFI-TT) project provides an alternative to animal models for assessing the toxic effects of chemical compounds on human development using induced pluripotent stem cells. Despite being expensive, time consuming, and offering limited insights into human biology, animal models are the current gold standard for toxicity testing. However, human cells can be used to generate models of early human development and, by using these models to assess toxic effects, human-relevant toxicity data may be more more controllable, repeatable, and inexpensive. Such an alternative to animal models could reduce the costs of drug and chemical development, and as regulatory groups worldwide set goals for the reduction and eventual elimination of animal testing, drug and chemical development companies will need to adopt effective and efficient alternatives. The few platforms for assessing toxicity that exist in the market rely on metrics that are inadequate for predicting human toxicity. As such, platforms that more faithfully model human development may have impact on the toxicity testing market space.The proposed project seeks to develop a novel human stem cell-based microfluidic developmental toxicology platform, in which three-dimensional multicellular models are generated for toxicity testing. This project aims to conduct critical technological developments for this microfluidic toxicology platform to make it repeatable, controllable, and high-throughput while thoroughly characterizing its predictive power. Specifically, this project aims to integrate microfluidic organoid-generation technology with automated and commercially-available liquid handling systems to minimize operator influence and enable future scale-up of the experimental platform via multiple integrated platforms running in parallel. Additionally, this project aims to validate the predictive power of the platform by using it to test the effects of a comprehensive suite of compounds with known toxicities. The testing may be used to determine the range of compounds for which the platform is predictive, as well as to examine the effects of each compound on tissue morphology, cell marker expression, and metabolism. This data will be used to determine the predictive power of each metric in order to develop efficient tools and endpoints to expedite toxicological assessment of experiments.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.

这一创新-技术转化伙伴关系项目的更广泛影响/商业潜力为使用诱导多能干细胞评估化合物对人类发育的毒性作用提供了动物模型的替代方法。尽管昂贵，耗时，并且对人类生物学的了解有限，但动物模型是目前毒性测试的黄金标准。然而，人类细胞可用于生成早期人类发育的模型，并且通过使用这些模型来评估毒性作用，与人类相关的毒性数据可能更加可控，可重复和廉价。这种动物模型的替代品可以降低药物和化学品开发的成本，随着全球监管机构制定减少和最终消除动物试验的目标，药物和化学品开发公司将需要采用有效和高效的替代品。市场上存在的用于评估毒性的少数平台依赖于不足以预测人类毒性的指标。因此，更忠实地模拟人类发育的平台可能会对毒性测试市场产生影响。拟议项目旨在开发一种新的基于人类干细胞的微流体发育毒理学平台，其中生成三维多细胞模型用于毒性测试。该项目旨在为这个微流体毒理学平台进行关键技术开发，使其具有可重复性，可控性和高通量，同时彻底表征其预测能力。具体而言，该项目旨在将微流体类器官生成技术与自动化和商用液体处理系统相结合，以最大限度地减少操作员的影响，并通过并行运行的多个集成平台实现实验平台的未来规模扩大。此外，该项目旨在通过使用该平台来测试一系列具有已知毒性的化合物的影响，来验证该平台的预测能力。测试可用于确定平台预测的化合物的范围，以及检查每种化合物对组织形态、细胞标志物表达和代谢的影响。这些数据将用于确定每个指标的预测能力，以开发有效的工具和终点，加快毒理学评估的实验。该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。