Microelectrode array (MEA) technology for functional assessment of novel 3D bioprinted human cardiac tissue models.

我们要求微电极阵列(MEA)系统开发和优化使用人诱导多能干细胞来源的心肌细胞(hiPSC-CM)的集成和预测性心脏筛查试验，该方法可以得到验证并用于商业可行的试验。该MEA系统将是UBC在体外使用人类心脏细胞来确定心脏电和机械功能的第一台设备。*设备的需求、紧迫性和适宜性：MEA技术是我们研究的核心(NSERC DG：离子通道复杂功能的生物物理阐明(2016-21)和CHRP：用于药物机制和疗效测试的新型3D生物打印人体心脏组织模型(2018-21))。MEA的使用将加快结果并改善这些NSERC计划的影响，因为它提供了一种高度敏感、数据丰富的方法，以高通量的方式研究时空分辨率的3D生物打印心脏组织的电活动。这项技术从细胞单层或细胞簇记录细胞外场电位，并产生场电位持续时间作为体外替代心电图QT间期的指标。目前，心脏电功能测试方法(即细胞和动物模型)不能准确预测正常的人类心脏生理或允许足够的药物发现所需的吞吐量。因此，显然有必要开发新的和强大的人体实验模型，以预测药物效果并促进高通量筛选。*研究计划的优点和研究团队的卓越表现：HiPSC-CM的无限来源为创建可用于药物作用机制(MOA)和疗效测试的健康人体心脏组织的体外模型提供了新的可能性。美国食品和药物管理局(FDA)旨在通过将预测性技术，包括商业上可用的HiPSC-CM，引入到药物MOA的评估中，以改善当前的监管指导。PI是心脏离子通道生物物理学领域的世界领先者，该项目将把心脏电生理学和细胞生物学方面的卓越成果与新型生物打印细胞支架和微流体的开发结合起来，与总部位于不列颠哥伦比亚省的成功3D生物打印技术公司Aspect BiosSystems合作创建可获得专利的HiPSC-CM模型。这项研究计划将得到功能完善的MEA系统的支持，作为验证应用于高通量筛选的新细胞模型的必要工具。将基于HiPSC-CM的3D组织与MEA相结合，将能够对电生理活动进行相关、准确、实时和灵活的测量，从而提供一种评估药物MOA的通用生物学工具。*高素质人员(HQP)：团队公平的HQP培训计划将培训1名硕士、2名博士、3名本科生和1名PDF。HQP将体现身份和不同种族和民族背景的多样化和代表性组合。

We request a microelectrode array (MEA) system to develop and optimize an integrated and predictive cardiac screening assay using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), which can be validated and used in a commercially viable assay. This MEA system will be the first apparatus available at UBC to determine cardiac electrical and mechanical function using human cardiac cells in-vitro.***Need, urgency and suitability of equipment: The MEA technology is central to our research (NSERC DG: Biophysical elucidation of ion channel complex function (2016-21) and CHRP: Novel 3D bioprinted human cardiac tissue models for drug mechanism and efficacy testing (2018-21)). Use of the MEA will accelerate outcomes and improve impact from these NSERC programs as it provides a highly sensitive, data-rich method to study the electrical activity of 3D bioprinted cardiac tissue with spatiotemporal resolution in a high throughput manner. This technology records extracellular field potentials from cell monolayers or clusters, and generates field potential duration as an in vitro surrogate for the QT interval of the electrocardiogram. Currently, cardiac electrical function testing methods (i.e., cellular and animal models) do not accurately predict normal human cardiac physiology or allow sufficient throughput needed for drug discovery. Thus, there is a clear need to develop new and robust human experimental models that predict drug effects and facilitate high-throughput screening.***Merit of the research program and excellence of the research team: The unlimited source of hiPSC-CM provides new possibilities to create in vitro models of healthy human cardiac tissue that can be used in drug mechanism of action (MOA) and efficacy testing. The Food and Drug Administration (FDA) aims to improve current regulatory guidance by introducing predictive technologies, including commercially available hiPSC-CM, into assessment of drug MOA. The PI is a world leader in cardiac ion channel biophysics and this program will combine excellence in cardiac electrophysiology and cell biology with the development of novel bioprinted cell scaffolds and microfluidics to create patentable hiPSC-CM models in collaboration with Aspect Biosystems, a successful BC-based 3D bioprinting technology company. This research program will be supported by the well-characterized MEA system as an essential tool to validate novel cell models for application to high throughput screening. Integration of hiPSC-CM based 3D tissue with MEA will enable relevant, accurate, real-time, and flexible measurement of electrophysiological activity, thereby providing a versatile biological tool to assess drug MOA.***Highly qualified personnel (HQP): The team's equitable HQP training plan will train 1 MSc, 2 PhD, 3 undergrad, and 1 PDF. HQP will exemplify a diverse and representative combination of identities and various racial and ethnic backgrounds.*****