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

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 coaxial 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 downregulated 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 multisysteminteractive organoid chip for finding precise therapeutic targets of IR injury.

Progress in the generation of spinal cord organoids over the past decade and future perspectives

Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.