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

这一创新技术转化伙伴关系(PFI-TT)项目的广泛影响/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影响的动物模型提供了一种替代方案。尽管动物模型昂贵、耗时，而且对人类生物学的洞察有限，但动物模型是目前毒性测试的黄金标准。然而，人类细胞可以用来建立人类早期发育的模型，通过使用这些模型来评估毒性影响，与人类相关的毒性数据可能更可控、更可重复、更便宜。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，随着世界各地的监管机构为减少并最终取消动物试验设定目标，药品和化学品开发公司将需要采用有效和高效的替代品。市场上现有的为数不多的毒性评估平台依赖于不足以预测人体毒性的指标。因此，更真实地模拟人类发育的平台可能会对毒性测试市场空间产生影响。拟议的项目旨在开发一种新型的基于人类干细胞的微流控发育毒理学平台，在其中生成用于毒性测试的三维多细胞模型。该项目旨在为这个微流控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。具体地说，该项目旨在将微流控类有机物产生技术与自动化和商业可用的液体处理系统相结合，以最大限度地减少操作员的影响，并通过多个并行运行的集成平台实现未来实验平台的扩大。此外，该项目旨在通过使用该平台测试一系列已知毒性的化合物的效果来验证该平台的预测能力。该测试可用于确定该平台预测的化合物的范围，以及检查每个化合物对组织形态、细胞标记表达和新陈代谢的影响。这些数据将被用来确定每个指标的预测能力，以便开发有效的工具和终点来加快实验的毒理学评估。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.