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

基本信息

批准号：
10688234
负责人：
Xueju Wang
金额：
$ 19.6万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
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：
2022-09-01 至 2025-05-31
项目状态：
未结题

项目摘要

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.

项目概要/摘要人体类器官是由三维 (3D) 培养物产生的微型器官模型系统体外组织驻留成体干细胞（ASC）或多能干细胞（PSC）。他们已经成为用于组织发育和疾病建模、个性化医学开发、药物的有前途的平台筛选和药物毒性研究。尽管潜力巨大，但目前的人类类器官仍面临着以下问题：类器官的结构和功能不成熟、异质性有限以及可访问的读数有限评估。例如，对这些 3D 生物系统的详细研究，如 3D 电生理学使用传统方法（例如两种方法）无法实现大脑和心脏类器官的绘图用于调制和多模态传感的二维 (2D) 多电极阵列 (MEA)。此外，大多数目前的生物系统缺乏体内存在的稳定且成熟的血管化，这对控制氧气、营养和神经模式因子等分子的输送，以增强类器官的大小，寿命和复杂性。我们的目标是开发一种用于在线的软电子/微流体混合 3D 网络人体类器官的监测、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，可同时传感、刺激和良好控制的输送分子进入深层组织以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）开发高时空多功能3D电子网络类器官功能在线监测和调节的解决方案，（2）开发仿生3D微血管用于 3D 组织血管化的网络，并将其与 3D 电子网络集成为混合体系统，以及（3）使用大脑在体外评估集成系统的效率和功能鲁棒性以类器官为例。我们提出的多功能混合系统包含以下值得注意的内容创新特点： 1) 用于电气、光学、电化学和热传感的柔软、可拉伸的 3D 网络和刺激人体类器官，2）用于人体血管化的仿生 3D 微血管网络类器官，3）完全集成的电子和微流体网络作为微型实验室，用于研究各种人类类器官的诱导行为和自然行为。这项工作将为研究神经发育开辟一条新途径通过同时监测、调节脑类器官和血管化来治疗神经系统疾病整个 3D 内部，这引起了神经科学界广泛的潜在兴趣。此外，开发的 3D 混合系统可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。