Multifunctional 3D Bioelectronic and Microfluidic Hybrid Systems for Online Monitoring, Regulation, and Vascularization of Organoids

用于在线监测、调节和类器官血管化的多功能 3D 生物电子和微流体混合系统

• 批准号: 10510946
• 负责人: Xueju Wang
• 金额: $ 25.16万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10510946
• 关键词: 3-Dimensional; Alzheimer' s Disease; Award; Behavior; Biochemical; Biological; Biological Models; Biomimetics; Biosensing Techniques; Blood Vessels; Brain; Brain Mapping; Cells; Characteristics; Collaborations; Communities; Culture Media; Development; Devices; Dimensions; Disease; Drug Screening; Drug toxicity; Electric Stimulation; Electronics; Electrophysiology (science); Evaluation; Geometry; Goals; Heart; Heterogeneity; Human; Hybrids; In Vitro; Investigation; Kidney; Light; Location; Longevity; Lung; Measurement; Mechanics; Microelectrodes; Microfluidics; Monitor; National Institute of Biomedical Imaging and Bioengineering; Neurosciences; Neurosciences Research; Online Systems; Optics; Organogenesis; Organoids; Oxygen; Pattern; Performance; Pharmacology; Pluripotent Stem Cells; Property; Public Health; Reaction Time; Regenerative Medicine; Regulation; Research; Resolution; Route; Stretching; Structure; Surface; System; Techniques; Thinness; Tissue Engineering; Tissue Model; Tissues; Vascularization; Work; adult stem cell; bioelectronics; biomaterial compatibility; body system; density; design; flexibility; improved; in vivo; induced pluripotent stem cell; innovation; interest; miniaturize; multi-electrode arrays; multidisciplinary; multimodality; nanofabrication; nervous system disorder; neural patterning; neural stimulation; neurodevelopment; new technology; nutrition; optogenetics; personalized medicine; polydimethylsiloxane; prevent; sensor; small molecule; spatiotemporal; three dimensional cell culture; tissue culture; two-dimensional

PROJECT SUMMARY/ABSTRACT Human organoids are miniaturized model systems of organs produced by three-dimensional (3D) cultures of tissue-resident-adult stem cells (ASCs) or pluripotent stem cells (PSCs) in vitro. They have emerged as a promising platform for modeling tissue development and disease, personalized medicine development, drug screening and drug toxicity investigations. Despite their great potential, current human organoids suffer from immature structure and functionality, limited heterogeneity, as well as limited accessible readouts for organoid evaluation. For example, detailed investigations of these 3D biosystems, such as 3D electrophysiological mapping for brain and heart organoids, cannot be achieved using conventional approaches such as two- dimensional (2D) multi-electrode arrays (MEAs) for modulation and multimodal sensing. Furthermore, most current biosystems lack stable and mature vascularization that exists in vivo, which poses challenges to controlled delivery of oxygen, nutrition, and molecules like neural patterning factors to enhance organoid size, lifespan, and complexity. Our goal is to develop a soft electronic/microfluidic hybrid 3D network for online monitoring, regulation, and vascularization of human organoids. The resulting system will integrate separately addressable electrical, optical, electrochemical, and thermal sensors and stimulators of designated locations with 3D biomimetic microvascular networks for simultaneous sensing, stimulation, and well-controlled delivery of molecules into deep tissues to study tissue development and modulation. We will achieve this goal through pursuing three specific aims: (1) Develop multifunctional 3D electronic networks with high spatiotemporal resolution for online monitoring and regulation of organoid function, (2) Develop biomimetic 3D microvascular networks for the vascularization of 3D tissues and integrate them with 3D electronic networks into a hybrid system, and (3) Evaluate the efficiency and functional robustness of the integrated system in vitro using brain organoids as an example. Our proposed multifunctional hybrid system incorporates the following notable innovative features: 1) Soft, stretchable 3D networks for electrical, optical, electrochemical, and thermal sensing and stimulation of human organoids, 2) Biomimetic 3D microvascular networks for the vascularization of human organoids, 3) Fully integrated electronics and microfluidics networks as a micro-lab for investigating various induced and natural behaviors of human organoids. This work will create a new route to study neurodevelopment and neurological disorders through simultaneous monitoring, regulation, and vascularization of brain organoids throughout their 3D interior, which is of broad potential interest to the neuroscience community. In addition, the developed 3D hybrid system can be applied to other types of organoids, including heart, lung, and kidney for in vitro studies of related diseases.

项目总结/摘要 人类类器官是通过三维（3D）培养产生的器官的小型化模型系统， 组织驻留成体干细胞（ASC）或多能干细胞（PSC）。他们已经成为一个 有前途的平台，用于组织发育和疾病建模，个性化药物开发，药物 筛选和药物毒性研究。尽管它们具有巨大的潜力，但目前的人类类器官遭受着 结构和功能不成熟，异质性有限，以及类器官读数有限 评价例如，这些3D生物系统的详细研究，如3D电生理学 脑和心脏类器官的映射不能使用常规方法实现，例如两个- 三维（2D）多电极阵列（MEA）用于调制和多模态感测。而且大多数 目前的生物系统缺乏体内存在的稳定和成熟的血管形成，这对 控制氧气、营养和神经模式因子等分子的输送，以增加类器官的大小， 寿命和复杂性。我们的目标是开发一个软电子/微流体混合3D网络， 人类类器官的监测、调节和血管化。由此产生的系统将单独集成 指定位置的可寻址电、光、电化学和热传感器和刺激器 具有3D仿生微血管网络，可同时感知、刺激和良好控制的输送 深入组织研究组织发育和调节。我们将通过以下方式实现这一目标 追求三个具体目标：（1）开发具有高时空的多功能3D电子网络 解决在线监测和调节类器官功能，（2）开发仿生三维微血管 用于3D组织血管化的网络，并将它们与3D电子网络集成为混合网络。 系统，以及（3）使用脑体外评估集成系统的效率和功能稳健性 以类器官为例。我们提出的多功能混合动力系统包括以下值得注意的 创新特性：1）用于电学、光学、电化学和热传感的柔软、可拉伸的3D网络 2）用于人类类器官血管化的仿生3D微血管网络， 3）完全集成的电子和微流体网络，作为研究各种生物的微型实验室 人类类器官的诱导和自然行为。这项工作将为研究神经发育开辟一条新的途径 通过同时监测、调节和血管化脑类器官， 在它们的3D内部，这是神经科学界广泛的潜在兴趣。此外该 开发的3D混合系统可以应用于其他类型的类器官，包括心脏，肺和肾脏， 相关疾病的体外研究。