The first adaptable, 3D-formfitting microelectrode array for organoid-based models of neurological and neurodegenerative diseases

第一个适应性强的 3D 贴合微电极阵列，用于基于类器官的神经系统和神经退行性疾病模型

• 批准号: 10584822
• 负责人: Oliver Graudejus
• 金额: $ 5.5万
• 依托单位: BMSEED, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584822
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Animal Model; Animals; Area; Biological Markers; Brain; Brain Diseases; Cardiac; Cardiovascular Diseases; Cell Culture Techniques; Cell physiology; Characteristics; Complex; Development; Dimensions; Disease; Disease model; Drug Screening; Electrodes; Electrophysiology (science); Equipment; Evaluation; Health Care Costs; Human; Image; In Vitro; Measures; Mechanics; Membrane; Microelectrodes; Modeling; Monitor; Morphologic artifacts; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurological Models; Noise; Organ; Organoids; Outcome; Parkinson Disease; Phase; Physiological; Physiology; Plant Roots; Pre-Clinical Model; Preclinical Drug Development; Problem Solving; Property; Protocols documentation; Reproducibility; Research; Resolution; Shapes; Signal Transduction; Site; Societies; Stretching; Structure; Suction; Surface; Technology; Thick; Tissues; Traumatic Brain Injury; Vacuum; Validation; Work; autism spectrum disorder; base; cell behavior; cellular imaging; drug candidate; drug development; drug efficacy; drug testing; elastomeric; electric impedance; electrical property; fluorescence microscope; human model; improved; in vitro Model; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; instrumentation; mechanical properties; model development; nervous system disorder; neural network; neurotransmission; novel; pre-clinical; pre-clinical research; pressure; relating to nervous system; therapy development; three-dimensional modeling; voltage

Abstract The proposed work aims at the development of an enhanced organoid-based in vitro pre-clinical drug screening platform for neurological and neurodegenerative brain diseases. 2D in vitro cell cultures and non- human animals have been the mainstay of pre-clinical drug development and mechanistic studies for decades. However, 2D cell cultures and animals do not accurately recapitulate the complexity and unique features of human physiology, thus behave differently from their in vivo and human counterparts in many key characteristics of cellular behavior, limiting our ability to accurately model brain diseases. Thanks to advancements in human induced pluripotent stem cell (hiPSC) technology, complex structures resembling developing organs, named organoids, have been generated for many types of organs, including brain organoids. These human organoids replicate critical organ and tissue-specific features not observed in animal models or 2D cell cultures, thus providing a unique opportunity to model human organ structure and function under healthy and disease conditions. A major limitation for brain organoid research is the lack of adequate instrumentation to monitor spatial and temporal organization of neural networks. Specifically, organoids are spherical whereas commercial microelectrode arrays (MEAs) are flat, which reduces the accuracy to determine neural network organization because the cellular surface area for recording neural signals is limited and organoids remodel on flat surfaces. To enhance the value of brain organoids for preclinical research and disease modeling, an MEA technology is needed that enables monitoring of neural signals across as much of the surface of the physiologically intact organoid as possible. No such commercial platform currently exists. This application aims to solve this problem by utilizing BMSEED’s stretchable microelectrodes to create pockets of variable sizes to contain the organoid, retain its shape and physiological function, and envelope it with microelectrodes for recording of neural activity across its surface. This novel 3D platform, the Organoid- Based Stimulating und Recording Vacuum Equipment (OBSuRVE), integrates three modules that (i) create the pockets in the adaptable contour for organoid research Multidimensional Electrode Array (conforMEA), (ii) record neural signals, and (iii) image cells and cellular processes. Specifically, this proposal has three aims. The first specific aim is focused on building the OBSuRVE platform, and to adapt the conforMEAs to meet the need for organoids research. The second specific aim is the evaluation of the electrical and mechanical properties of the platform. The third specific aim is the validation of the OBSuRVE platform for drug screening and disease modeling using brain organoids. The focus of this proposal are human brain organoids because neurological and neurodegenerative diseases, such as Autism, Alzheimer’s Disease, and Parkinson’s Disease, are among the most prevalent and costly health problems facing our society. However, the results will be applicable to other types of organoids, e.g., cardiac spheroids, for cardiovascular disease models as well.

抽象的 拟议的工作旨在开发增强的基于器官的体外临床前药物 神经和神经退行性脑疾病的筛查平台。 2D体外细胞培养和非 - 数十年来，人类动物一直是临床前药物开发和机械研究的支柱。 但是，2D细胞培养物和动物并未准确概括 人类生理学，因此在许多关键中的体内和人体和人类的行为不同 细胞行为的特征，限制了我们准确地模拟脑部疾病的能力。谢谢 人类诱导多能干细胞（HIPSC）技术的进步，类似于复杂的结构 已经为许多类型的器官生成了开发器官，包括大脑 器官。这些人类器官复制临界器官和组织特异性特征，在动物中未观察到 模型或2D细胞培养物，从而提供了一个独特的机会来建模人体器官结构和功能 在健康和疾病状况下。脑器官研究的主要限制是缺乏足够的 监测神经网络的空间和临时组织的仪器。具体而言，类器官是 球形，而商业微电极阵列（MEA）是平坦的，这降低了确定的准确性 神经网络组织，因为用于记录神经信号的细胞表面积有限，并且 类器官在平面上重塑。为了增强脑器官对临床前研究的价值和 疾病建模，需要一种MEA技术，该技术能够监视跨大部分的神经信号 尽可能完整的器官表面。目前没有这样的商业平台。 该应用程序旨在通过使用BMSEED的可拉伸微电极来解决此问题 可变尺寸的口袋包含器官，保留其形状和身体功能，并包围它 带有微电极用于记录其表面神经活动的。这个新颖的3D平台，例如 基于刺激和记录真空设备（痴迷），整合了三个模块（i）创建 器官研究多维电极阵列（Conformea），（ii）的适应性轮廓中的口袋 记录神经信号，以及（iii）图像细胞和细胞过程。具体来说，该提议具有三个目标。 第一个具体目的是集中于建立困扰平台，并适应构象以满足 需要器官研究。第二个特定目的是评估电气和机械 平台的属性。第三个具体目的是验证毒品筛查的困扰平台 和使用脑官的疾病建模。该提议的重点是人脑器官，因为 神经和神经退行性疾病，例如自闭症，阿尔茨海默氏病和帕金森氏病， 是我们社会面临的最普遍，最昂贵的健康问题之一。但是，结果将是 适用于其他类型的器官，例如心脏球体，也适用于心血管疾病模型。