by University of Virginia

Hydrogel fabrication and subcutaneous implantation. Credit: Science Advances (2024). DOI: 10.1126/sciadv.adf2675

A study from the University of Virginia’s Department of Biomedical Engineering has identified a critical mechanism driving fibrosis, or scarring, in response to medical implants made with biomaterial hydrogels.

Their discovery, published in the June 14 issue of Science Advances, offers new hope for improving the longevity and function of implant devices such as sensors, stents and drug delivery systems. The paper is titled “A Thy-1-negative immunofibroblast population emerges as a key determinant of fibrotic outcomes to biomaterials.”

The researchers, led by biomedical engineering assistant professor Daniel Abebayehu, associate professor Donald R. Griffin and professor Thomas H. Barker, found that a specific population of cells, known as Thy-1-negative immunofibroblasts, are key players in the formation of scar tissue around implants.

This scar tissue, called fibrotic encapsulation, is the body’s attempt to protect itself from foreign objects, but it often leads to implant failure by blocking the device’s function.

By studying an advanced type of material called microporous annealed particle hydrogels implanted in mice, the researchers discovered something surprising. Normally, the “MAP” hydrogels—which were co-invented by Griffin—integrate with the body, while avoiding a scar formation around it. However, when a specific protein called Thy-1 was removed from the mice, even these materials triggered scar formation.

Based on Barker’s previous research, the team already knew Thy-1 acts as a kind of brake in the body’s natural healing process, preventing fibroblasts—the cells that form tissue structures—from going into overdrive and creating thick, harmful scar tissue. But they didn’t know what causes fibroblasts to lose Thy-1 in response to an implanted material.

Thy-1 and Inflammation

Theorizing inflammation was to blame, they treated fibroblasts with inflammatory proteins and discovered only a specific group of fibroblasts lost Thy-1.

“What was quite interesting was that those cells are also uniquely characterized by immune-related genes,” Abebayehu said. “We’ve seen these ‘inflammatory fibroblasts’ occur in some diseases, like cancer or liver cirrhosis. Seeing them show up around biomaterials enclosed in a scar-like capsule was fascinating.”

Identifying the Thy-1 negative inflammatory fibroblasts is one more piece in the complex puzzle of fibrotic diseases, for which there are no cures.

Daniel Abebayehu, an assistant professor at the UVA School of Engineering and Applied Science, led a team that discovered why scarring forms around medical implants. Credit: Todd Wright, University of Virginia School of Engineering and Applied Science

“We know chronic inflammation is connected to fibrosis but we don’t know exactly how they’re related,” Abebayehu said.

Based on their findings, the team believes persistent inflammation initiates fibrosis by causing fibroblasts, like the Thy-1-negative subset, to emerge. These cells erroneously sense tissue stiffness, activating more scarring.

“This Thy-1 negative ‘flavor’ of inflammatory fibroblasts could bridge the gap between chronic inflammation and fibrosis,” Abebayehu said. “It’s possible the cells take over for inflammation in driving the scarring process, which might be why anti-inflammatory therapies have never worked for some scar-related diseases.”

Transforming patient care

Targeting these specific cells or the signals that drive their transformation, could prevent implant failure for millions of patients who need them, from heart devices to joint replacements.

Complications and the need for follow-up surgeries could be drastically reduced, but there are broader implications, too, Barker said.

“Fibrosis contributes to nearly half of all deaths in the developed world,” he said. “Better understanding of how the process starts and what sustains it could lead us to treatments that can stop it—something we don’t have today.”

Next steps

The team will continue to explore new or modified biomaterial designs that promote the presence of Thy-1 in fibroblasts. This could make implants that currently cause fibrosis become nonfibrotic and lead to more materials that, like Griffin’s MAP hydrogels, not only prevent scarring but promote healing and regeneration of healthy tissue.

The team also is working to identify all cell types and the different “flavors” they come in that emerge around biomaterial implants that elicit fibrosis, Abebayehu said.

“This will help us identify how inflammatory fibroblasts emerge, who they’re communicating with, and hopefully, how they lead to full-on fibrosis.”