Collaborative Research: Transforming Cardiotoxic Drug Screening Using Bioprinted Myocardial Tissue Model with Self-Sensing Capacity

心脏毒性是药物毒性的一个主要部分，因此对用于非心血管药物治疗的药物的心血管安全性有相当大的关注。传统的药物筛选方法，如使用二维细胞培养和动物模型，有明显的局限性。需要一些方法来制造更可靠地再现人体生理结构和功能的心脏组织模型。对于心脏毒性试验，监测模型组织对药物反应的行为同样重要，理想情况下是无标签和非侵入性的方式。本研究项目的目标是开发一种用于心脏毒性筛选的工程化心脏组织模型，以促进药物筛选和个性化医疗。三维模型的设计涉及嵌入柔软和可拉伸微电子的心脏组织，可以连续测量组织内的心脏毒性。这个项目的结果可以通过准确预测人类对候选药物的反应来显著降低药物开发的成本。这项研究还可以帮助减少药物筛选中动物模型的使用。该计划将提供机会，向K-12学生，特别是来自弱势群体的学生推广STEM教育，并向公众传播科学和工程知识。该研究项目旨在开发一种多材料、立体光刻生物打印的心脏组织模型，该模型具有嵌入式柔软和可拉伸的微电子。主要的研究思路是机械匹配的软微电子和生物打印心脏模型的无缝集成，将允许实时连续、原位和组织内测量心脏毒性以及对药物化合物的反应。项目参与者将进行实验和分析研究，以设计、优化、制造、表征和验证杂交心脏组织模型。具体步骤包括：1)优化工程微血管化心脏组织模型的设计和制造，以实现其在体内的结构和功能相似性；2)设计、分析、制造和测试软的、可拉伸的微电子；3)将软微电子与生物打印的心脏组织集成，形成杂交心脏组织模型。4)组织内微电子学诱导电生理和机械跳动信号的药物筛选研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cardiotoxicity represents a major segment of drug toxicities, so there are considerable concerns about the cardiovascular safety profile of drugs used for non-cardiovascular medication. Conventional drug screening approaches, such as using a 2-dimensional cell culture and animal models, have notable limitations. Approaches are needed to fabricate cardiac tissue models that more reliably reproduce human physiology with respect to their structure and function. For cardiotoxicity assays it is equally important to monitor the behavior of the model tissue in response to drugs, ideally in a label-free and non-invasive manner. The goal of this research project is to develop an engineered cardiac tissue model for cardiotoxicity screening that will facilitate drug screening and personalized medicine. The design of the 3-dimensional model involves cardiac tissues that are embedded with soft and stretchable microelectronics that can continuously measure cardiotoxicity within the tissue. The outcomes of this project could lead to significant cost reductions for drug development by accurately predicting human responses to drug candidates. The research also could help reduce the use of animal models for drug screening. The project will provide opportunities to promote STEM education for K-12 students, especially those from under-represented groups, and to disseminate science and engineering knowledge to the public.This research project aims to develop a multi-material, stereolithographically-bioprinted cardiac tissue model with embedded soft and stretchable microelectronics. The main research idea is that seamless integration of mechanically matched soft microelectronics and bioprinted cardiac models will allow for continuous, in situ and intra-tissue measurements of cardiotoxicity in real time and in response to pharmaceutical compounds. The project participants will conduct experimental and analytical studies to design, optimize, fabricate, characterize and validate the hybridized cardiac tissue model. Specific steps include 1) optimizing the design and fabrication of the engineered microvascularized cardiac tissue model to achieve structural and functional similarity to its in vivo counterpart, 2) designing, analyzing, fabricating, and testing soft, stretchable microelectronics, 3) integrating the soft microelectronics with the bioprinted cardiac tissue to form hybridized cardiac tissue model, and 4) studying the screening of a panel of drugs with induced electrophysiological and mechanical beating signals from the intra-tissue microelectronics.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.