Cai Hongwei, Tian Chunhui, Chen Lei, Yang Yang, Sun Alfred Xuyang, McCracken Kyle, Tchieu Jason, Gu Mingxia, Mackie Ken, Guo Feng
Department of Intelligent Systems Engineering, Indiana University Bloomington, Bloomington, IN 47405, USA.
Duke-NUS Graduate Medical School, Signature Research Program in Neuroscience and Behavioral Disorders, 8 College Road, Singapore 169857, Singapore.
Cell Stem Cell. 2025 May 1;32(5):824-837.e5. doi: 10.1016/j.stem.2025.02.010. Epub 2025 Mar 17.
Organoids, 3D organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present vascular network-inspired diffusible (VID) scaffolds to mimic physiological diffusion physics for generating functional organoids and phenotyping their drug response. Specifically, the VID scaffolds, 3D-printed meshed tubular channel networks, successfully engineer human midbrain organoids almost without necrosis and hypoxia in commonly used well plates. Compared with conventional organoids, these engineered organoids develop more physiologically relevant features and functions, including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared with conventional organoids with significant diffusion limits. This platform may provide insights for organoid development and therapeutic innovation.
类器官是源自干细胞的三维器官样组织培养物，在发育生物学、药物发现和再生医学方面显示出广阔的潜力。然而，当前类器官的功能和表型，尤其是神经类器官，仍然受到氧气、营养物质、代谢产物、信号分子和药物扩散不足的限制。在此，我们提出了受血管网络启发的可扩散（VID）支架，以模拟生理扩散物理过程，从而生成功能性类器官并对其药物反应进行表型分析。具体而言，VID支架是通过3D打印的网状管状通道网络，在常用的微孔板中成功构建了几乎没有坏死和缺氧现象的人类中脑类器官。与传统类器官相比，这些工程化类器官具有更多生理相关的特征和功能，包括中脑特异性特征、氧代谢、神经元成熟和网络活动。此外，与具有显著扩散限制的传统类器官相比，这些工程化类器官还能更好地重现药理反应，如暴露于芬太尼时神经活动的变化。该平台可能为类器官发育和治疗创新提供见解。
