Microfluidic intestinal organoid-on-a-chip uncovers therapeutic targets by recapitulating oxygen dynamics of intestinal IR injury

• Published in: Bioactive materials Vol. 30; pp. 1 - 14
• Main Authors: Huang, Jinjian, Xu, Ziyan, Jiao, Jiao, Li, Zongan, Li, Sicheng, Liu, Ye, Li, Ze, Qu, Guiwen, Wu, Jie, Zhao, Yun, Chen, Kang, Li, Jieshou, Pan, Yichang, Wu, Xiuwen, Ren, Jianan
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.12.2023; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Ionic barrier of ZIF-8; Microfluidics; Olfm4; Organoid-on-a-chip; Oxygen dynamics; Organoid-on-a-chip; Olfm4; Oxygen dynamics; Microfluidics; Ionic barrier of ZIF-8
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2023.07.001

Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24 h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury. Illustration. In this study, we developed a new generation of multi-system interactive microfluidic intestinal organoid-on-a-chip to achieve fast oxygen kinetics matching with intestinal IR injury in vivo. Based on the chip, Olfm4 was screened and confirmed to be an effective therapeutic target for intestinal IR injury. [Display omitted] •Constructing tissue engineering scaffolds for artificial blood vessels based on the pH-responsive ionic barrier effect of MOFs.•Developing a microvascularized intestinal organoid-on-a-chip to achieve fast oxygen kinetics imitating intestinal IR injury.•Based on the chip, Olfm4 was screened as an effective therapeutic target for intestinal IR injury.