Signaling system in cells detects mismatch between implant stiffness and natural tissue, then triggers a cycle of scarring and inflammation
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Every year, millions of people live fuller lives because of a medical device implanted somewhere in their body. From hip joints, to teeth, to heart valves, these devices represent $90.5 billion to the global economic market according to industry researchers, and that number is expected to grow as technology improves and the population ages. So, it’s a major concern of the medical industry that human bodies frequently reject implanted devices, and there are no consistently effective strategies to prevent or suppress it.
Known as Foreign Body Response (FBR), inflammation and scarring around an implant is natural, but in some cases, it can severely damage healthy tissue and can 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 understand the underlying biology that causes FBR.
Now, researchers from the University of Maryland have discovered the molecular basis for FBR, identifying a key biological pathway that future drug therapies could target to reduce the risk of implant rejection.
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 identified a specific cellular signaling system that kicks in when the body recognizes the inherent difference in stiffness between an implant and the surrounding tissue. This system detects the mismatch and triggers inflammation and scarring, which is part of the body’s normal defense system. But in FBR, the signaling system can set up a cycle of chronic inflammation and continual scar-tissue build-up 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 things like fibrosis in the lungs or scarring around a wound—a specific receptor in nearby cells becomes activated. This receptor, called TRPV4, is part of the body's intricate signaling system that can sense a cell's physical environment and trigger responses that control things like blood pressure, heart rate and even perception of temperature and touch.
To Rahaman and his team, the activation of the TRPV4 receptor in association with fibrosis, inflammation, and other tissue stiffening processes suggests that TRPV4 may play a role in FBR, because biomedical implants are generally stiffer than the host tissue they are implanted into.
“When you implant a biomedical device—a breast implant, knee implant, heart valve—there will be an inherent mismatch in the stiffness or rigidity of the implant and your body tissue,” Rahaman explained. “Our work shows that the TRPV4 receptor senses this mismatch and sets off an inflammatory cycle that leads to stiffening of the tissues around the implant, and that leads to more activation of this receptor which leads to more stiffening, in a vicious feedback loop.”
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 (which is the basis of scar tissue) built up around stiffer implants than around softer implants that mimicked the stiffness of natural skin. In the genetically modified mice, stiffness of implants made no difference in collagen build-up, which was minimal and similar to the build-up on the soft implant in normal mice.
The researchers also found that in normal mice nine times more inflammatory cells called macrophages accumulated on the stiffer implants than the softer ones, while fewer macrophages accumulated on either type of implant surface in the genetically modified mice.
These experiments suggest two possible strategies for reducing implant rejection. 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 material for hip implants and heart valves, and silicone best mimics breast tissue.)
Another strategy might be to 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. The receptor is present in many different types of cells, and it is critical to things like wound healing and maintaining proper blood pressure. So, Rahaman and his team are now drilling down further into the molecular pathways to identify which specific cells the TRPV4 that signals the foreign body response is coming from.
They believe TRPV4 in macrophages may be the culprit since those cells accumulate on implant surfaces and are known to drive a host of inflammatory processes.
“We have developed mice in which only macrophage TRPV4 is absent,” Rahaman said. “Our next steps will be to continue our experiments to understand if macrophage TRPV4 is involved in driving the foreign body response.”
Perhaps new therapies to prevent medical implant rejections will involve blocking TRPV4 only in macrophages, or disrupting the downstream processes that TRPV4 causes. Whatever it turns out to be, scientists now have a target to begin aiming for.
This paper, titled “Mechanosensing by TRPV4 mediates stiffness-induced foreign body response and giant cell formation,” was published in the journal Science Signaling.
Other authors from UMD include postdoctoral fellows Rishov Goswami and Rakesh K. Arya, and graduate students Shweta Sharma and Bidisha Dutta from the Department of Nutrition and Food Science, and Professor and Chair of the Department of Veterinary Medicine, Xiaoping Zhu. In addition, co-author Dimitar R. Stamov is from JPK BioAFM Business Berlin Germany: Dimitar R. Stamov,
This work was supported by the National Institutes of Health (Award No: R01EB024556) This story does not necessarily reflect the views of this organization.
* UPDATE, August 2022: Since this story was published, NIH has awarded a $3.5 million/5 years R01 grant for continuation of this work to Shaik O. Rahaman (Department of Nutrition and Food Science) and his co-Principal Investigators: Xiaoping Zhu (Department of Veterinary Medicine), Xiaoming He (Department of of BioEngineering), Srinivasa R. Raghavan (Department of Chemical Engineering), and Jonathan Bromberg (UMD Medical School). This is the competing renewal of Rahaman's previous R01 grant to study impacts of a microRNA and calcium-permeable channel on foreign body response, a chronic inflammatory disease.