March 28, 2017

Blocking scar tissue formation around medical device implants

At a Glance

  • Researchers discovered the molecular pathway for scar tissue formation around medical implants.
  • Blocking the pathway in animal models prevented scar tissue from forming around several implanted materials.
  • A therapy targeting this pathway might prevent scar tissue around medical device implants in people. 
Illustration of macrophage The immune system often builds up a wall of dense scar tissue around implanted medical devices, a process known as fibrosis. The cell shown in blue represents a macrophage that has been blocked from initiating fibrosis. Felice Frankel

Millions of Americans have pacemakers, knee replacements, drug delivery devices, and other implants in their bodies. Unfortunately, the immune system recognizes medical device implants as foreign. In a process known as fibrosis, immune cells protect the body by walling off the foreign material in a thick capsule of scar tissue. The scar tissue raises the risk of early failure and the need for replacement.

The precise mechanism of fibrosis isn’t known. People at risk may be prescribed medicine that blocks the immune system. A more specific drug that could target a specific fibrosis pathway would minimize the broad effects of dampening immune responses.

A team led by Dr. Daniel G. Anderson of the Massachusetts Institute of Technology devised a series of experiments to determine the immune cells and pathways involved in fibrosis. The work was funded in part by NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institute of Dental and Craniofacial Research (NIDCR), and National Cancer Institute (NCI). Results were published online on March 20, 2017, in Nature Materials.

Medical device implants are made from biocompatible materials, such as ceramic glass, metal alloys, certain plastics, and biogels. The team implanted alginate gel microspheres into animal models. They used models representing a range of immune depletions to tease out the immune pathway for fibrosis. They selected alginate because fibrosis is an important reason for failure of medical implants made with this material.

Two weeks after implantation, the researchers removed the microspheres. As expected, a white plaque of scar tissue covered the spheres. The plaque consisted of 3 types of immune cells: macrophages, neutrophils, and B cells. Mice without functional macrophages proved to be the only animal model without implant-induced fibrosis. Depletion of macrophages in other mice also eliminated fibrosis, showing that macrophages were required for the process.

The researchers next analyzed the expression of genes involved in mouse immune system signaling. A macrophage-specific factor called colony stimulator factor-1 receptor (CSF1R) appeared to be involved in scar formation. The team thus tested a small molecule called GW2580 that specifically inhibits CSF1R. GW2580 prevented scar tissue around implants made of alginate, ceramic glass, and polystyrene plastic. Perhaps most important, it didn’t impair other macrophage functions.

“This gives us a better understanding of the biology behind fibrosis and potentially a way to modulate that response to prevent the formation of scar tissue around implants,” Anderson says.

Anderson’s team has been developing a treatment for diabetes using alginate to encapsulate insulin-producing cells. Fibrosis has been a barrier to success. They aim to apply these findings to advance the development of the diabetes treatment.

—by Geri Piazza

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References: Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Doloff JC, Veiseh O, Vegas AJ, Tam HH, Farah S, Ma M, Li J, Bader A, Chiu A, Sadraei A, Aresta-Dasilva S, Griffin M, Jhunjhunwala S, Webber M, Siebert S, Tang K, Chen M, Langan E, Dholokia N, Thakrar R, Qi M, Oberholzer J, Greiner DL, Langer R, Anderson DG. Nat Mater. 2017 Mar 20. doi: 10.1038/nmat4866. [Epub ahead of print]. PMID: 28319612.

Funding: NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institute of Dental and Craniofacial Research (NIDCR), National Cancer Institute (NCI), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Juvenile Diabetes Research Foundation; Leona M. and Harry B. Helmsley Charitable Trust Foundation; and Tayebati Family Foundation.