I-Corps: In Vitro Cardiac Platform for Drug Discovery and Cardiotoxicity Screens

这个i-Corps项目的更广泛的影响/商业潜力是为潜在的心脏治疗开发一个药物发现测试平台。目前，大多数药物发现测试开始于在传统细胞培养环境(例如培养皿)中筛选新药或治疗药物。然而，这并不能充分代表人体内的真实生物学背景。这在针对心脏病的治疗中尤其如此，在心脏病治疗中，细胞通常受到心脏每秒跳动的动态运动。这项拟议的技术旨在利用心脏组织筛选平台推进下一代心脏病药物的研发。该平台旨在使用电磁控制和自动视频跟踪来提供生理上相关的机械环境，以便将组织暴露在体内经历的机械力中。这样的工具可能对制药公司、合同研究组织和临床心脏病学实践/医院系统具有潜力。最终，更好的发现工具可能会带来更好的疗法，以改善人类的健康和福祉。这个i-Corps项目基于心脏组织培养技术的开发，旨在模拟心脏跳动的机械环境，用于药物发现应用。该平台的拟议设计使用计算机控制的电磁体，使三维心脏组织具有动态力-长度关系。其目标是匹配心脏在各种心脏疾病情况下经历的压力和容量变化，如高血压和主动脉瓣狭窄。此外，该平台还可以产生与疾病相关的指标，如组织硬度、收缩性、每搏功和心输出量曲线，这些指标直接转化为临床相关的诊断指标和结果指标。其目的是通过使组织受到充分的机械压力来提供现有方法所不具备的关键优点。生理上正确的机械环境可能会提高治疗筛查的成功率，而生理上相关的输出指标可能有助于证明临床可译性。此外，动态机械环境可以在所需的测试条件下提供实验多功能性(例如，正常与压力过载与体积过载力学)。该奖项反映了NSF的法定使命，并已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 I-Corps project is the development of a drug discovery testing platform for potential heart treatments. Currently, most drug discovery testing begins with screening a new drug or therapeutic in traditional cell culture environments (e.g., petri dishes). However, this does not adequately represent the real biological context inside the human body. This is especially true for therapies targeting heart disease, where the cells are normally subjected to dynamic motion from the heart beating every second. The proposed technology aims to advance the next generation of heart disease medications using a cardiac tissue screening platform. The platform is designed to provide a physiologically relevant mechanical environment using electromagnetic controls and automated video tracking in order to expose tissues to the mechanical forces experienced within the body. Such a tool may hold potential for pharmaceutical companies, contract research organizations, and clinical cardiology practices/hospital systems. Ultimately, better discovery tools may lead to better therapies for improving human health and well-being.This I-Corps project is based on the development of heart tissue culture technology designed to mimic the mechanical environment of a beating heart for drug discovery applications. The proposed design of this platform uses computer-controlled electromagnets to subject 3-dimensional cardiac tissues to dynamic force-length relationships. The goal is to match the pressure and volume changes experienced by the heart in various heart disease conditions such as hypertension and aortic valve stenosis. In addition, the platform can produce disease-relevant metrics such as tissue stiffness, contractility, stroke work, and cardiac output curves, which directly translate to clinically relevant diagnostic metrics and outcome measures. The aim is to provide key merits that are not provided with existing approaches by subjecting tissues to full mechanical pressure. A physiologically correct mechanical environment may improve the success of therapy screens while physiologically relevant output metrics may help demonstrate clinical translatability. In addition, a dynamic mechanical environment may provide experimental versatility under desired testing conditions (e.g., normal vs. pressure-overload vs. volume-overload mechanics).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.