Multiplexed quantitative measurements of field potential and contractility on biomimetically-matured hPSC-CMs

对仿生成熟 hPSC-CM 的场电位和收缩性进行多重定量测量

基本信息

批准号：
9910089
负责人：
Nicholas Andrew Geisse
金额：
$ 22.5万
依托单位：
CURI BIO INC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910089
关键词：
Address Adoption Arrhythmia Biochemical Biological Biological Assay Biomimetics Cardiac Cardiac Myocytes Cardiotoxicity Cell Culture Techniques Cell Shape Cells Clinical Trials Communities Consumption Cost efficiency Cues Data Detection Development Devices Drug Screening Electrical Resistance Electrodes Electrophysiology (science)End Point Assay Environment Extracellular Matrix Failure Frequencies Geometry Health Heart Human In Vitro Industry Standard Measurable Measurement Measures Mechanics Methods Microelectrodes Microscopy Mission Morphology Optics Pattern Pharmaceutical Preparations Phase Phenotype Physiological Platinum Polymers Process Property Proxy Research Resources Speed Stem cells Stretching Structure Surface Techniques Technology Testing Therapeutic Thinness Time Tissues Traction Force Microscopy Translations Work base bench to bedside biomaterial compatibility cost design drug candidate drug development electric impedance electrical measurement extracellular high throughput screening improved induced pluripotent stem cell innovation instrument mechanical properties medication safety nanofabrication nanofiber nanopattern novel novel therapeutics polydimethylsiloxane pre-clinical response scale up sensor success tissue culture tool

项目摘要

PROJECT SUMMARY The development of new drugs is a costly and time-consuming process (~$2.5 billion over 5-10 years) with a very low success rate where only 1 out of 10,000 candidates will ever reaches the market. One of the leading causes for this issue is the cardiotoxicity of drug candidates, wherein a drug has an off-target effect of causing cardiac arrhythmias. As a result, significant effort and resources have been allocated to create more predictive preclinical and in vitro drug screening platforms. Human derived induced pluripotent cardiac myocyte stem cells (hPSC-CMs) are a promising tool to address this problem, but their relative lack of phenotypic maturity remains a barrier to their wide adoption. Some platforms focus on mimicking the structural (e.g. biomimetic cultureware), mechanical (e.g. cell and tissue stretching devices), and electrochemical (e.g. microelectrode array platforms) cues of the extracellular matrix of the tissue to improve hPSC-CM maturity. While these cues are vital to the tissue development, they are oftentimes incompatible with the high-throughput assays that are required by drug developers. Further, measuring maturity within an assay is a challenge. Contractility is considered to be a highly- accurate method of measuring maturity, state of differentiation, and general health of cardiomyocytes. The currently available measurement tools cardiomyocytes (CMs) contractility can be generally grouped as either impedance-based or microscopy-based (such as traction force microscopy; TFM). Impedance-based measurements are often fast and accurate but lacking in terms of capturing quantitative information, as impedance measures only cell shape changes and uses that as proxy of the cell contraction. In contrast, TFM techniques are capable of quantifying CM contraction, but it is laborious and incompatible with high-throughput platforms. Indeed, a critical need of the research community is a multiplexed platform that measures contractility in a high-throughput and quantitative fashion in an environment that applies extracellular cues to drive the development and maturity of CMs. NanoSurface Biomedical’s mission is to develop a first-of-its kind microelectrode array device that provides a biomimetic culture environment and is multiplexed with quantitative contractility measurement. We term this device the “MP-ForceMEA”. The MP-ForceMEA will use an innovative strain-gauge sensor with an MEA platform and will represent a novel instrument capable of simultaneous detection of electrophysiology and contractility in a highly parallel, high-throughput, and scalable manner. Phase 1 activities will result in the development of a single-well novel platform compatible with standard end-point assays, and this work will then serve as the basis for progression into Phase 2, where the device will be scaled up to high-throughput assay formats. The resulting work will greatly improve the cost, efficiency, and safety of drug development and speed to market new lifesaving drugs.

项目概要新药的开发是一个昂贵且耗时的过程（5-10 年约 25 亿美元），成功率非常低，只有万分之一的候选人能够进入市场。造成这个问题的原因是候选药物的心脏毒性，因此药物具有脱靶效应，导致因此，人们投入了大量的精力和资源来创建更具预测性的心律失常。临床前和体外药物筛选平台。人源诱导多能心肌细胞干细胞。（hPSC-CM）是解决这一问题的有前途的工具，但它们的表型成熟度仍然相对缺乏一些平台专注于模仿结构（例如仿生文化器皿），机械（例如细胞和组织拉伸装置）和电化学（例如微电极阵列平台）组织细胞外基质的线索可提高 hPSC-CM 成熟度，而这些线索对于 hPSC-CM 成熟度至关重要。组织发育，它们通常与药物所需的高通量测定不相容此外，测量测定中的成熟度被认为是一项高度挑战。测量心肌细胞成熟度、分化状态和总体健康状况的准确方法。目前可用的测量工具心肌细胞（CM）收缩力通常可分为以下几类：基于阻抗或基于显微镜（例如牵引力显微镜；TFM）。测量通常快速且准确，但缺乏捕获定量信息的能力，例如阻抗仅测量细胞形状变化，并将其用作细胞收缩的代表。技术能够量化 CM 收缩，但它费力且与高通量不兼容事实上，研究界的一个关键需求是测量收缩性的多重平台。在应用细胞外线索驱动的环境中以高通量和定量的方式 NanoSurface Biomedical 的使命是开发首创的 CM。提供仿生培养环境并与定量复用的微电极阵列装置我们将该设备称为“MP-ForceMEA” MP-ForceMEA 将使用一种创新技术。具有 MEA 平台的应变计传感器将代表一种能够同时以高度并行、高通量和可扩展的方式检测电生理学和收缩性。 1 项活动将导致开发与标准终点兼容的单井新颖平台这项工作将作为进入第二阶段的基础，其中设备将进行扩展由此产生的工作将极大地提高成本、效率和安全性。药物开发和新救生药物的上市速度。