The results of studies by researchers at the University of Arizona College of Medicine – Tucson suggest that an immune cell-specific protein called RAC2 may drive a process known as foreign-body response (FBR), by which the body can sometimes reject biomedical implants such as pacemakers and orthopedic hardware. The investigators showed that either pharmacologic or genetic inhibition of the Rac2 gene in a mice model significantly reduced this FBR response. The team hopes that the discoveries will help to improve the design and safety of biomedical implants.
Senior author Geoffrey Gurtner, MD, FACS, department chair of surgery, and co-lead author Kellen Chen, PhD, assistant research professor of surgery, and team, reported on their study in Nature Biomedical Engineering, in a paper titled “Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.” In their paper the investigators concluded, “Overall, our findings contribute to the better understand[ing] of the FBR, provide a mechanistic target to prevent the development of a pathological FBR, and may have substantial implications for the design and safety of implantable medical devices in humans.”
Biomedical implants, such as breast implants, pacemakers and orthopedic hardware, have transformed medicine, and more than 70 million devices are implanted globally every year, the authors wrote. However, a significant number are rejected by the body and need to be removed. The culprit is a little-understood immune reaction called foreign body response, or FBR, in which the body encapsulates the implant in scar tissue, leading to device malfunction.
“Chronic inflammation around implanted devices leads to reduced biocompatibility and results in the development of a long-term foreign-body response (FBR),” the team noted. “In clinical practice, the longevity of biomedical implants is limited by a pathological FBR, frequently leading to implant failure and eventual rejection.” The more severe the immune reaction, the thicker the capsule. In some people, this capsule constricts around the implant, impeding its function and causing pain. In fact, FBR is associated with 90% of all implant failures in commonly used medical devices, and up to 30% of implants need to be removed due to FBR.
It’s widely thought that the FBR may be primarily a reaction of the local host tissue to the chemical and mechanical surface properties of the implanted material, but there is still an incomplete understanding of the mechanism, at least in part because of a lack of standard animal models that can recapitulate the sustained inflammatory response and severe fibrotic reaction that is associated with implant failure in humans, the authors continued. “Although the molecular machinery responsible for inflammation and fibrosis is highly conserved across species, studies have shown that small animal models, such as mice, generate a relatively mild FBR to implantable materials compared with larger organisms, such as humans, which limits their clinical relevance.”
To help gain a better understanding of why some immune systems build thick capsules around implants while others do not, Gurtner, Chen and colleagues gathered capsule samples from 20 patients whose breast implants were removed—10 whose reactions were severe, and 10 whose reactions were mild. They found that a protein called RAC2 was highly expressed in samples taken from patients with severe reactions.
“When we examined the severe fibrotic samples, RAC2 was one of the most important proteins we found,” Chen said. “Because it seemed to drive a lot of downstream pathways, we decided to explore a little more closely.”
Using a newly developed mouse model the investigators found that in reaction to mechanical stress caused by the implants, immune cells activate RAC2 and other proteins, which summon additional immune cells, including those types that can combine to attack a large invader. “That foreign body, which is very stiff and causes stress on the external environment, activates these immune cells to aggregate to that area,” Chen said. “They start merging with each other, making massive cells that spit out fibrous proteins like collagen and other products.”
To confirm RAC2’s role in FBR, the team then blocked the expression of RAC2 in animal models. “We targeted RAC2 along with other pathways and observed a significant reduction in the level of FBR—up to three-fold,” said Dharshan Sivaraj, PhD, research fellow in the Department of Surgery and co-lead author of the study. “Taken together, these results show that blocking Rac2 signalling in immune cells can cause a cascade of downstream effects, including significantly decreased myofibroblast differentiation, reduced downstream collagen production and mitigated FBR capsule formation,” the team noted. “In short, by blocking the immune orchestrators of FBR, it is possible to reverse the human-like FBR resulting from increased levels of extrinsic tissue-scale forces in mice.”
Chen said that in contrast to the prevailing hypothesis that FBR is a reaction to the chemical composition of the implant, the new study demonstrates that the implant introduces stress points to the body, triggering an overactive immune response. “The cells touch this new material similar to if I touch something soft versus something hard. My body can tell that a table is harder than a pillow—touching the table activates mechanical pathways in my fingers. Similarly, as the cells interact with that implant and surrounding tissue, they activate due to the increased mechanical stress,” Chen said. “The immune cells realize there is a foreign body there, and they react by building a fibrotic capsule that surrounds the implant in an attempt to shield it off.” Gurtner added, “Establishing a complete understanding of the molecular mechanisms driving the foreign body response presents the final frontier in developing truly bio-integrative medical devices,” Gurtner said.
RAC2 is specific to immune cells, which means that, theoretically, a drug blocking it might only target immune cells without affecting other cells in the body. “We think targeting these pathways could serve as a potential therapy to mitigate or even prevent clinically significant FBR in humans,” Sivaraj continued. Gurtner and Chen, who are also members of the UArizona Cancer Center, are already working with the Arizona Center for Drug Discovery at the R. Ken Coit College of Pharmacy to develop a drug candidate.
Tech Launch Arizona, the University of Arizona’s technology commercialization office, is working with the team to translate the innovation from the laboratory to the marketplace, where they hope it will have real-world impact for patients and their health care providers.
Gurtner added, “We believe that local targeted therapy is better. Maybe there are ways to conjugate this drug onto an implant with some sort of coating to minimize systemic problems.” The authors continued, “For example, future biomedical implants could have a coating of the inhibitor, and systemic therapy could also be investigated.”
The Gurtner Lab conducted this study in collaboration with teams at Stanford University School of Medicine, the University of Texas Southwestern Medical Center, and University Hospital Regensburg in Germany.