UMD Scientists ID Molecular Culprit in Medical Implant Rejections

Every year, millions of people live fuller lives because of medical devices implanted in their bodies, from replacement hip joints to teeth to heart valves. But with the global $90.5 billion market for such devices only expected to grow as the population ages, understanding why our bodies frequently reject implanted devices is important—and University of Maryland researchers have found a key insight in the effort to stop it.

The inflammation and scarring around an implant known as Foreign Body Response (FBR) is natural, but in some cases can severely damage healthy tissue and even lead to death if the implant is not removed. FBR-related implant failure rates range widely among different medical devices, but reducing those rates has been difficult because scientists still don’t fully understand the underlying biology of FBR.

Now, Shaik O. Rahaman, an associate professor in the Department of Nutrition and Food Science in the College of Agriculture and Natural Resources at UMD, and his colleagues have identified a cellular signaling system that kicks in when the body recognizes the inherent difference in stiffness between an implant and the surrounding tissue. As explained in a paper in Science Signaling, the system then triggers inflammation and scarring as part of the body’s normal defense system against foreign objects—think splinters. But in FBR, the signaling system can set up a cycle of chronic inflammation and continual scar-tissue buildup that leads to implant rejection.

“This is a huge leap forward in this field,” Rahaman said. “So far, the medical industry has been making biomedical implants randomly, out of materials they think might work without knowing the molecular basis of the foreign body response that leads to rejection. We don’t know why it happens, and until we do, we can’t effectively develop strategies to prevent it.”

Rahaman’s team previously noted that when natural tissues in the body stiffen—because of conditions like fibrosis in the lungs or scarring around a wound—a specific receptor known as TRPV4 in nearby cells becomes activated, suggesting that it may also play a role in FBR.

To test their hypothesis, the researchers implanted cellulose discs into two different sets of mice: one normal, the other genetically modified to lack the gene for producing TRPV4.

The experiments revealed that in normal mice, 4.5 times more collagen (the basis of scar tissue) built up around stiffer implants than around softer implants that mimicked the stiffness of natural skin. They also found that in normal mice, nine times more inflammatory cells called macrophages accumulated on the stiffer implants than the softer ones. Genetically modified mice had far less reaction to all kinds of implants.

These experiments suggest two possible strategies: Scientists could develop implants with materials that are closer to natural tissue in stiffness, although the technology to do that remains limited. (For now, titanium remains the best option for hip implants and heart valves, and silicone best mimics breast tissue.) Or, they could disrupt the body’s signaling system for recognizing a stiff foreign body.

That won’t be as simple as developing drugs to block or eliminate TRPV4, which is present in many types of cells and critical to wound healing and maintaining proper blood pressure. Rahaman and his team are currently exploring whether TRPV4 in macrophages, specifically, may be the ultimate culprit driving FBR.