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Human intestine on-a-chip: state-of-the-art and into the future

Recent advances in human intestinal Organ Chip technology reviewed by the Wyss Institute team

The mechanically active human Gut Chip. The human intestinal epithelium with its villi-like structure and human vascular endothelium are lined on opposite sides of a flexible membrane under flow and peristalsis-like motions (purple arrows). This engineered intestinal microenvironment undergoes complex interactions (indicated by the blue arrows in the zoom-in schematic on the bottom) with commensal gut microbiome, bacterial pathogens, and immune cells. Credit: Wyss Institute at Harvard University

Modeling physiological and pathophysiological processes in the human intestinal tract outside the human body has been a daunting challenge for bioengineers. Different regions exhibit different digestive, absorptive and protective barrier functions. Through resident immune and neuronal cells, they communicate with the immune system and the brain; and they each interact in specific ways with the commensal microbiome – the bacterial community inhabiting the gut. As an additional challenge, it also has become clear that the intestinal tract relies on mechanical peristalsis movements to develop its complex organization and various functions.

Yet, to more profoundly understand how specific diseases including inflammatory and infectious diseases, cancer, or inherited disorders affect the gut, and to be able to identify and study new drugs in a close-to-natural context, more faithful and accessible human in vitro systems are urgently needed.

Researchers have resorted to relatively simple cell culture systems in which human intestinal cell lines are grown on a porous membrane within so-called Transwell chambers to study barrier and transport functions. They even have modeled more complex 3D tissue constructs, known as intestinal organoids, using cells from intestinal crypts of patients or patient-specific induced pluripotent stem cells (iPSCs). However, these systems still fall short of mimicking the intestine’s more complex morphology and physiology. They remain static due to the absence of peristalsis movements, lack important cell types like blood vessel-forming endothelial cells and immune cells, and do not have a normal intestine lumen that experiences fluid flow and is easily accessible to analysis. As a result, many studies involving, for example, drug and nutrient transport, or the interaction between the intestine and living commensal microbial communities cannot be performed in the experimental models.

These challenges have recently been overcome using microfluidic Organ-on-a-Chip (Organ Chip) technology.  The Intestine Chip models contain mechanically active, continuously perfused microchannels inhabited by different human intestinal cell populations that form tissues with in vivo-like morphologies, which can be functionally interfaced with each other, the living intestinal microbiome and immune system. In a recent article published in Cellular and Molecular Gastroenterology and Hepatology, the Wyss Institute team led by Founding Director Donald Ingber, M.D., Ph.D., which pioneered Organ Chip technology and has been at the forefront of developing next-generation microfluidic human Organ Chip models, including of the intestine, reviews the state-of-the-art of this field and the potential of using human intestinal Organ Chip technology for disease modeling, drug development and personalized medicine.

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