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A micromachining fluidic cantilever for single cell advanced patch clamping and cellular characterization using atomic force microscopy

使用原子力显微镜进行单细胞先进膜片钳和细胞表征的微加工流体悬臂

基本信息

批准号：
10615901
负责人：
Ami Chand
金额：
$ 80.52万
依托单位：
APPLIED NANOSTRUCTURES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615901
关键词：
Academia Action Potentials Address Adhesives Affect Area Atomic Force Microscopy Biological Biological Assay Biological Markers Biological Sciences Biology Biomedical Research Cardiac Myocytes Cardiology Cardiotoxicity Cell Therapy Cell surface Cells Clinical Consumption Development Devices Disease Doctor of Philosophy Drug Evaluation Elasticity Electrodes Electronics Electrophysiology (science)Endocrinology Event Failure Feedback Functional disorder Genetic Heart Diseases Hour Human In Vitro Individual Industry Ion Channel Ions Laboratories Laboratory Technicians Learning Libraries Marketing Masks Measurement Measures Membrane Potentials Microbiology Microelectrodes Modality Muscle Fibers Nanostructures Nanotechnology Neurology Neurons Neurosciences Patients Performance Pharmaceutical Preparations Pharmaceutical Solutions Pharmacologic Substance Phenotype Population Property Publishing Pump Reaction Records Research Research Personnel Resolution Safety Scanning Probe Microscopes Scientist Small Business Innovation Research Grant Spectrum Analysis Structure of beta Cell of islet System Techniques Technology Testing Time Tissue Sample Toxic effect Training assessment application cantilever consumer demand design drug candidate drug discovery elastography electrical property heart cell heart function improved induced pluripotent stem cell medical schools meter nanomachine novel therapeutics patch clamp personalized medicine pharmacologic response seal sensor tool validation studies viscoelasticity

项目摘要

Single patch clamping is used to multiple areas of biology such as cardiology (cardiomyocytes), neurology/neuroscience (neurons), endocrinology (pancreatic beta cells), myology (muscle fibers), and even microbiology (bacterial ion channels). Applied Nanostructures (AppNano) in partnership with the Icahn School of Medicine is bringing to the market a unique solution addressing a major market need in electrophysiology measurements. With its advanced features and unmatched resolution, the device will enable researchers in academia and in the highly competitive life sciences industry to answer important scientific questions and develop and test new drugs fueling the discovery of new pharmaceutical solutions. As a result, these companies will be better equipped to keep up with the ever-increasing consumer demand for pharmaceutical products. In this SBIR we are developing a semi-automated system based on an micro-electromechanical systems (MEMS) sensor pipette used with atomic force microscopes (AFM) that can measure, simultaneously and directly, electrophysiological properties (such as action potentials (AP)), contractile forces on single cardiomyocytes (CM), and single cell elasticity. This system offers high content analysis (HCA) at a single cell level. The system enables a significant increase in performance and a dramatic decrease in time to complete a measurement. With times <5 min compared to conventional patch clamping (2-4 hours) achieved by leveraging micromachining and advanced atomic force microscopy (force spectroscopy). The proposed system will simplify patch clamping measurements and require minimal training. This system will make it reasonably easy for any laboratory technician to conduct these measurements, in contrast to conventional patch clamping, which has a steep learning curve and requires a PhD-level scientist. In addition to action potential and contraction force, we can also evaluate the viscoelastic and adhesive properties of the cells. Our device will be capable of addressing a critical bottleneck in drug discovery that arises during the final characterization of drug candidates. The device can detect single cell changes that would otherwise be masked when averaged over large populations, offering the advantage of measuring rare events, such as toxicity indicators that affect the beating phenotype or action potential (AP) of subpopulations of CMs. This tool finds applications in: drug evaluation/discovery, in the study of Cardiomyocytes (CM) derived from human induced pluripotent stem cells (CM-iPSCs), as a general patch- clamping tool, and in clinical settings. In the setting of personalized medicine, for example, the tool allows for interrogation of enough iPSC-CM (generated from a patient’s tissue sample for instance) to produce statistically meaningful results within several minutes that would indicate an individual’s reaction to a specific drug. Additionally this tool finds application in the study to other types of cardiotoxic effects and in other fields of biomedical research that use electrophysiology (patch clamping), such as neuroscience/neurology and endocrinology.

单膜片钳用于生物学的多个领域，例如心脏病学（心肌细胞）、神经学/神经科学（神经元）、内分泌学（胰腺β细胞）、肌肉学（肌纤维），甚至微生物学（细菌离子通道）。应用纳米结构 (AppNano) 与伊坎学院合作 of Medicine 正在向市场推出一种独特的解决方案，满足电生理学的主要市场需求测量。凭借其先进的功能和无与伦比的分辨率，该设备将使研究人员能够学术界和竞争激烈的生命科学行业回答重要的科学问题和开发和测试新药，推动新药物解决方案的发现。结果，这些公司将更好地满足消费者对药品不断增长的需求。在在此 SBIR 中，我们正在开发一种基于微机电系统 (MEMS) 的半自动化系统传感器移液器与原子力显微镜（AFM）一起使用，可以同时直接测量，电生理特性（如动作电位 (AP)）、单个心肌细胞的收缩力（CM）和单细胞弹性。该系统提供单细胞水平的高内涵分析 (HCA)。系统能够显着提高性能并显着减少完成测量的时间。和与通过利用微机械加工实现的传统膜片钳（2-4小时）相比，时间<5分钟先进的原子力显微镜（力谱）。所提出的系统将简化膜片钳测量并需要最少的培训。该系统将使任何实验室都相当容易技术人员进行这些测量，与传统的膜片钳相比，其具有陡峭的学习曲线并需要博士学位级别的科学家。除了动作电位和收缩力之外，我们还可以还评估细胞的粘弹性和粘附特性。我们的设备将能够解决候选药物最终表征过程中出现的药物发现的关键瓶颈。该设备可以检测单细胞的变化，否则这些变化在对大量群体进行平均时会被掩盖，从而提供测量罕见事件的优势，例如影响跳动表型或行为的毒性指标 CM 亚群的潜力 (AP)。该工具可应用于：药物评估/发现、研究中源自人类诱导多能干细胞（CM-iPSC）的心肌细胞（CM），作为通用补丁- 夹紧工具，以及在临床环境中。例如，在个性化医疗的背景下，该工具允许询问足够的 iPSC-CM（例如从患者的组织样本生成）以产生统计数据几分钟内即可得出有意义的结果，表明个人对特定药物的反应。此外，该工具还可用于其他类型的心脏毒性作用的研究以及其他领域使用电生理学（膜片钳）的生物医学研究，例如神经科学/神经学和内分泌学。