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Fine-Tuning Organ-Chip Technology

Scientists Develop a New Method to Better Visualize and Analyze Multicellular Interactions

A new method developed by scientists at Cedars-Sinai makes it easier to visualize the cell populations in organ chips, the technology that recapitulates true-to-life biology outside the body.

Chip on left with no clearing (opaque strip of cells in middle) and after clearing (translucent strip of cells).Induced pluripotent stem cell and organ-chip technologies are increasingly being combined as a platform to study various diseases and test drug therapies. While the organ chip has improved disease modeling, it can still be challenging to visualize cellular components—including proteins—on the chip due to the increased tissue density and opacity.

To overcome these challenges, investigators have created a method that uses multiple tissue-clearing techniques to enhance the visualization of cells with antibody staining. 

The method is detailed in the peer-reviewed journal Lab on a Chip

"This new protocol allows researchers to image thicker tissue with the organ chips at higher resolution and clarity, improving our ability to see multicellular interactions," said senior author of the study Clive Svendsen, PhD, professor of Biomedical Sciences and Medicine and executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

Cedars-Sinai pioneered combining organ-chip technology with a patient's own stem cells. It re-creates the body's microenvironment with the natural physiology and mechanical forces that cells experience within the human body.

The living cells can form a part of the body, such as the blood-brain barrier or intestine, that functions as it does in the body. Drugs then can be tested on the cells to predict the most effective disease treatments based on a patient's unique biology.

While developing blood-brain barrier chip models of neurological diseases, researchers in the Svendsen Laboratory found the conventional staining techniques did not provide the resolution needed, due to issues with antibody and light penetration into the deeper parts of the chip.

The team decided to try adapting a tissue-clearing protocol that is used for mouse brains for the organ-chip modeling system. 

"We were able to successfully reduce and optimize the protocol and apply tissue clearing to the organ chip," said first author Briana Ondatje, a research associate in the Svendsen Laboratory. 

An image of astrocytes, neurons and microglia in the chip after clearing.In addition, the scientists developed a way to generate and stain multiple tissue slices through the chip, allowing more information to be gained from a single chip experiment.  

"Combining enhanced tissue clearing and multiple slices through the chip can help the organ-chip field advance and provides a fantastic view of the cellular interactions within these living human systems," said Svendsen, who is also the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine. "This can be very beneficial for systems, such as the brain and gut, where tissue grows to multiple thick layers. We are very excited by this development and hope it will help others in the field."

Other Cedars-Sinai authors in this study are Samuel Sances and Michael Workman.

Research for this study was supported in part by the National Institutes of Health under award number 1UG3NS105703-01 and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. 

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