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

• 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
• 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

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.

项目摘要 新药的开发是一个昂贵且耗时的过程（5 - 10年内约25亿美元） 成功率非常低，其中只有10,000名候选人中只有1个将进入市场。领导之一 该问题的原因是候选药物的心脏毒性，其中毒品具有促靶向的效果 心律不齐。结果，已经分配了巨大的努力和资源来创造更多的预测性 临床前和体外药物筛查平台。人衍生的诱导多能心肌细胞干细胞 （HPSC-CMS）是解决此问题的有前途的工具，但它们相对缺乏表型成熟度仍然存在 他们广泛采用的障碍。一些平台专注于模仿结构（例如仿生培养软件）， 机械（例如细胞和组织拉伸设备）和电化学（例如，微电极阵列平台） 组织外基质的提示，以改善HPSC-CM成熟度。这些提示对 组织的发展，它们通常与药物要求的高通量测定法不相容 开发人员。此外，测量评估中的成熟度是一个挑战。收缩性被认为是高度的 测量成熟度，分化状态和心肌细胞一般健康的准确方法。这 当前可用的测量工具心肌细胞（CMS）的收缩力通常可以分为 基于阻抗或基于显微镜的基于牵引力显微镜； TFM）。基于阻抗 测量通常是快速而准确的，但在捕获定量信息方面缺乏，如 阻抗仅测量细胞形状的变化，并将其用作细胞收缩的替代。相反，TFM 技术能够量化CM收缩，但它是实验室，并且与高通量不相容 平台。实际上，研究界的迫切需要是一个多路复用的平台，可以衡量收缩力 在应用细胞外提示的环境中，以高通量和定量方式驱动 CMS的发展和成熟度。纳米表面生物医学的使命是开发一种首先 微电极阵列设备，提供仿生培养环境，并用定量多重 收缩度测量。我们将此设备称为“ MP-Forcemea”。 MP-Forcemea将使用创新 带有MEA平台的应变规格传感器，将代表一种能够简单的新型仪器 以高度平行，高通量和可扩展的方式检测电生理学和收缩力。阶段 1个活动将导致开发与标准终点兼容的单孔小说平台 测定法，这项工作将作为发展为2阶段的基础，将设备缩放 最多可高通量测定格式。最终的工作将大大提高成本，效率和安全性 药物开发和销售新的救生药物的速度。