Research News

For decades, researchers and physicians alike have blamed intestinal fibrosis on inflammation, but with one complication. Anti-inflammatory drugs don't give patients with inflammatory bowel disease (IBD) relief from painful intestinal scarring. Researchers from the laboratory of Cleveland Clinic's Hyun Jung Kim, PhD created an organ-on-a-chip to ask why anti-inflammatory medication doesn't work, and discovered a surprising answer: inflammation may not be the main culprit after all.

The Advanced Science publication shows that the forces and stresses associated with bowel movements themselves can physically damage cells deep in the colon, especially when the cells lining the surface of the intestine are compromised. This damage leads to scarring and fibrosis in the tissue underneath.

“Keeping the gut lining strong may be just as important as fighting inflammation which might be the missing piece in why current therapies don't always work,” Dr. Kim says.

What is an organ-on-a-chip?

An organ-on-a-chip is a small piece of silicone patterned with microscopic grooves, chambers and tubes that mimic the structure and function of an organ in 3D. Organs on chips are some of the most advanced technologies researchers can perform relevant experiments at a lab bench.

Each part of the chip is lined with different cell types that make up the organ, organized to match its real-life counterpart. Because the cells can be taken directly from patients, organs on chips let researchers and clinicians create and test personalized systems tailored to anyone’s unique condition or needs.

The Kim Lab developed a gut-on-a-chip that lets them accurately simulate the inside of an intestine. The silicone base matches the flexibility of real colon tissue, and the researchers can mimic -- and test -- the force and motions associated with bowel movements.

“We are not trying to make a fancy, expensive toy. A lot of engineering, physics, biology and math goes into making sure the chips are implementable and predictable," Dr. Kim says.

What happens to colon cells to cause fibrosis?

Study first author and Kim Lab Research Associate Soyoun Min, PhD, used different types of colon cells from patients with and without ulcerative colitis to make different guts-on-chips. She focused on two main cell types:

1. Fibroblasts: cells found deep within the tissue. They make collagen and other proteins to heal wounds, keep the tissue flexible and provide structural support. During fibrosis, fibroblasts accumulate and form painful, unflexible scars.
2. Epithelial cells: cells that line the surface of the colon, producing mucus daily. These cells physically touch waste products as they move through the colon. They act as barrier cells that protect fibroblasts and the rest of the tissue.

Dr. Min simulated the force and pressure of bowel movements in her chips to see if fibrosis scarring could be caused by physical force instead of through chemical signals (inflammation).

She found that in a healthy gut, epithelial cells act as protective shields. Deeper tissues and fibroblasts are unaffected by fluid shear stress from the luminal side. However, epithelial cells from individuals with IBD were compromised. They were physically weaker and more prone to damage. These epithelial cells couldn’t protect the fibroblasts below from the physical force of simulated bowel movements.

When exposed to the force of liquid flowing over an impaired epithelial barrier, even healthy fibroblasts activated and started forming scar tissue.

A study in persistence

The Kim Lab’s findings open the door to new forms of therapies that focus on the epithelial barrier instead of inflammation. Dr. Kim says that these new ways of thinking came from an observation that initially looked like failure.

When Dr. Min first began culturing fibroblasts on the gut-on-a-chip system, the healthy fibroblast cells would detach and die whenever she tried to simulate a bowel movement. She worried she was doing something wrong.

“After multiple times with the same outcome, we realized this wasn’t a mistake or a failure,” Dr. Kim says. “Something biological was happening.”

Instead of giving up, Dr. Min asked what the cells were doing just before they died. She found biological signals showing that even healthy fibroblasts were vulnerable to mechanical stress and needed something to protect them. These findings led her to add epithelial barrier cells to the chip.

“If we had just said, ‘This isn’t working’ and moved on, we would have missed the entire discovery,” Dr. Kim says. “The key was not letting go when something didn’t make sense.”

For Dr. Kim, Dr. Min’s persistence is just as important to the story as her findings themselves.

“Not all discoveries come from the results you expected,” he says. “They come from results that force you to stop and look closer.”