Study Examines How Breast Implant Surfaces Affect Immune Response

Researchers are narrowing in on how breast implant surfaces may affect immune response and influence the development breast implant-associated large cell lymphoma (BIA-ALCL), and their findings may pave the way toward safer breast implants.

"The surface topography of an implant can drastically affect how the immune response perceives it, and this has important ramifications for the [implants'] design," says study author Omid Veiseh, an assistant professor of bioengineering at Rice who began the research six years ago during a postdoctoral fellowship at MIT. "We hope this paper provides a foundation for plastic surgeons to evaluate and better understand how implant choice can affect the patient experience."

The study appears in Nature Biomedical Engineering.

Veiseh, whose lab focuses on developing and studying biocompatible materials, says he is particularly excited about the discovery that surface architecture can be tuned to reduce host immune responses and fibrosis to breast implants.  "There's a lot we still don't understand about how the immune system orchestrates its response to implants, and it is really important to understand that within the context of biomaterials," Veiseh says in a news release.

"Clinically, we have observed that patients exposed to textured-surface breast implants can develop breast implant-associated large cell lymphoma (BIA-ALCL), but this has not occurred with smooth-surface implants," adds Mark Clemens, MD an associate professor of plastic surgery at MD Anderson who leads a multidisciplinary treatment team on the disease. "This paper gives important novel insights into cancer pathogenesis with clear implications for preventing disease before it develops."

Veiseh adds that the work also provided important clues that will guide follow-up studies.

"That's the most exciting part of this: it could lead to safer, more compatible biomaterials and implant designs," Veiseh says

Surface analysis

Silicone breast implants have been in use since the 1960s. The earliest versions had smooth surfaces, but patients with these implants often experienced a complication called capsular contracture, in which scar tissue formed around the implant and squeezed it, creating pain or discomfort as well as visible deformities. Implants could also flip after implantation, requiring surgical adjustment or removal.

In the late 1980s, some companies introduced rougher surfaces intended to reduce capsular contracture rates and make implants stay in place. The textured surfaces have peaks of varying heights. The peaks of some average hundreds of microns.

In 2019, the FDA requested breast implant manufacturer Allergan recall highly textured breast implants that had an average surface roughness of about 80 microns due to risk of BIA-ALCL.

In 2015, Veiseh and Joshua Doloff , then postdocs in the lab of MIT's Robert Langer, began testing five commercially available implants with different surface designs to see how they would interact with surrounding tissue and the immune system. These included the highly textured one that had been previously recalled, one that was completely smooth and three that were somewhere in between.

Experimental results

In a study of rabbits, the researchers found tissue exposed to the more heavily textured implant surfaces showed signs of increased activity from macrophages. All of the implants stimulated immune cells called T cells, but in different ways. The study found implants with rougher surfaces stimulated more pro-inflammatory T cell responses. Among the non-smooth implants, those with the smallest degree of roughness (4 microns) stimulated T cells that appeared to inhibit tissue inflammation.

The findings suggest that rougher implants rub against surrounding tissue and cause more irritation. This may explain why the rougher implants can lead to lymphoma: The hypothesis is that some of the texture sloughs off and gets trapped in nearby tissue, where it provokes chronic inflammation that can eventually lead to cancer.

The researchers also tested miniaturized versions of implants in mice. They manufactured these implants using the same techniques used to make human-sized versions and showed that more highly textured implants provoked more macrophage activity, more scar tissue formation and higher levels of inflammatory T cells. The researchers worked with the Courtney Hodges lab at Baylor College of Medicine in Houston to perform single-cell RNA sequencing of immune cells from these tissues to uncover the specific signals that made the immune cells more inflammatory.

"The surface properties of the implants have profoundly different effects on key signals between immune cells that help recognize and respond to foreign materials," says Hodges, an assistant professor of molecular and cellular biology at Baylor. "The results show that the lightly textured surface avoided the strong negative cytokine immune response induced by the rough surface."

Toward safer implants

After their animal studies, the researchers examined how human patients respond to different types of silicone breast implants by collaborating with MD Anderson on the analysis of tissue samples from BIA-ALCL patients.

 They found evidence of the same types of immune responses observed in the animal studies. For example, they observed that tissue samples from patients that had been host to highly textured implants for many years showed signs of a chronic, long-term immune response. They also found that scar tissue was thicker in patients who had more highly textured implants.

"Doing across-the-board comparisons in mice, rabbits and then in human [tissue samples] really provides a much more robust and substantial body of evidence about how these compare to one another," Veiseh explains.   The authors hope their datasets will help other researchers optimize the design of silicone breast implants and other types of medical silicone implants for better safety.

"We are pleased that we were able to bring new materials science approaches to better understand issues of biocompatibility in the area of breast implants," says Langer, the study's senior author and MIT's David H. Koch Institute Professor. "We also hope the studies that we conducted will be broadly useful in understanding how to design safer and more effective implants of any type."

The research was funded by Establishment Labs. Langer, Hancock, Bayat, Kinney and Perry are members of the scientific advisory board of Establishment Labs and hold equity in the company. Sforza and Munhoz are members of the medical advisory board of Establishment Labs and hold equity in the company. Clemens is an investigator on the US IDE Clinical Trial for the Study of Safety and Effectiveness of Motiva Implants. De Mezerville, Romero, Elizondo and Leiva are employees of Establishment Labs and hold equity in the company. Doloff and Veiseh are paid Establishment Labs consultants.

PHOTO CAPTION: Rice University bioengineer Omid Veiseh shows silicone breast implants with rough (left) and smooth surfaces. (Photo by Jeff Fitlow/Rice University)