Article by Ella Kopplin, Julie Leonard-Duke & Katherine Cunningham

Developing Vascular Networks for Organoids-on-a-Chip

Source Publication: 

A microfluidic platform integrating functional vascularized organoids-on-chip, Nature Communications, 2024, Quintard et al., Xavier Girdol lab

Organoids are miniature, simplified versions of human organs grown in a laboratory. They are valuable tools for studying biology and disease, but keeping them alive for long periods of time in culture can be difficult. In organoids thicker than about 400 micrometers, oxygen and nutrients cannot reach the inner portions. Without a vascular system to both deliver these essential components and remove waste and carbon dioxide, the cells in these areas die. Creating a vascularized system to support these tissues has proven to be extremely challenging. In this study, researchers aimed to solve this problem by creating a microfluidic platform to functionally vascularize organoids on a chip.

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What did these researchers do?

The researchers created a microfluidic chip, a system that precisely controls small amounts of fluids, with ten S-shaped microchannels for fluid to flow through as well as a larger “trap” in each microchannel to hold the organoids. To construct microchannels that mimic vasculature, they covered the inner surface of the microchannel with a thin layer of endothelial cells, which form the inner lining of blood vessels.

In the body, endothelial cells self-organize to develop primitive vascular networks. The researchers wanted to see if their platform similarly encouraged endothelial cells to establish these connections in culture. They found that the platform successfully supported the growth of interconnected, tube-like vessel structures between the cells lining the microchannel (vascular bed) and the entrapped organoids. Importantly, these tiny vessels were able to carry fluid, confirming functionality. The researchers were also interested in whether the platform could improve development and function of different organoids. They found that providing both a vascular bed and flow of nutrients enhances the growth and maturation of blood vessel organoids and functionality of pancreatic islet spheroids.

Why is this important?

Organoids are derived from stem cells, which are cells that have the potential to become many different cell types. By providing stem cells with different cues, researchers can guide these cells to differentiate into specific types of cells, allowing them to then generate specific types of organoids. Because these organoids are made of human tissues, they can be used to model human development, study diseases, and test drugs. They can provide more relevant results than animal models or experiments that use only a single cell type. However, when organoids grow to a certain size, they often need to be transplanted into a living animal to establish a vascular system. This new microfluidic platform can help solve that problem by helping organoids grow their own functional vessel networks in the lab, allowing the organoids to mature, function better, and survive longer. The platform is also customizable, as the amount of fluid flow through the chip can be precisely controlled to mimic conditions in the body, and the size of the trap site can be modified to accommodate different 3D tissues.

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How did the researchers do this?

To set up the platform, the researchers first loaded a hydrogel with endothelial cells and an organoid. Hydrogels are soft, water-rich materials that provide a supportive environment for cells. This hydrogel starts as a liquid and is then activated to turn into a solid gel once it has flowed into place. As the hydrogel and organoid make their way through the channel, the organoid is captured in the trap site while the surrounding space is filled with the hydrogel. Before the hydrogel solidified, the researchers ran air through the channel to clear out the inside of the tube, leaving a thin layer of hydrogel and endothelial cells on the channel walls. Once the endothelial-lined channel was established, they perfused the growth medium, containing nutrients for the organoid and cells, through the system with a syringe pump. With the organoid and hydrogel in place, the researchers were then able to observe how the organoid connected to the vascular network and functioned.