When medical devices such as pacemakers are implanted in the body, they typically trigger an immune response that leads to the buildup of scar tissue around the implant. This scarring, known as fibrosis, can interfere with the functioning of the devices and may require their removal.
In a breakthrough that could prevent such device failures, MIT engineers have found a simple, general way to eliminate fibrosis by coating the devices with a hydrogel adhesive. This adhesive bonds the devices to the tissue and prevents the immune system from attacking it.
“The dream of many research groups and companies is to implant something in the body that in the long term the body will not see, and the device can provide therapeutic or diagnostic functionality. Now we have that ‘invisibility cloak,’ and this is very general “There’s no need for a drug, there’s no need for a special polymer,” says Xuanhe Zhao, a professor of mechanical engineering and civil and environmental engineering at MIT.
The adhesive the researchers used in this study is made of cross-linked polymers called hydrogels and is similar to a surgical tape they previously developed to help seal internal wounds. The researchers found that other types of hydrogel adhesives can also protect against fibrosis, and they believe this approach could be used not only for pacemakers but also for sensors or devices that deliver drugs or therapeutic cells.
Zhao and Hyunwoo Yuk SM ’16, PhD ’21, a former MIT research scientist who is now SanaHeal’s chief technology officer, are lead authors of the study, which will appear in Nature. MIT postdoc Jingjing Wu is the lead author of the paper.
Preventing fibrosis
In recent years, Zhao’s lab has developed adhesives for a variety of medical applications, including single- and double-sided tapes that could be used to heal surgical incisions or internal injuries. These adhesives work by quickly absorbing water from wet tissues, using polyacrylic acid, an absorbent material used in diapers. Once the water is cleared, chemical groups called NHS esters embedded in the polyacrylic acid form strong bonds with proteins on the surface of the fabric. This process takes about five seconds.
Several years ago, Zhao and Yuk began exploring whether this type of adhesive could also help keep medical implants in place and prevent fibrosis.
To test this idea, Wu coated polyurethane devices with his adhesive and implanted them in the abdominal wall, colon, stomach, lungs, or heart of rats. Weeks later, they removed the device and discovered there was no visible scar tissue. Additional tests with other animal models showed the same thing: wherever the adhesive-coated devices were implanted, no fibrosis occurred for up to three months.
“This work has really identified a very general strategy, not just for one animal model, one organ or one application,” Wu says. “In all of these animal models, we have consistent and reproducible results without any observable fibrotic capsule.”
Using massive RNA sequencing and fluorescent imaging, the researchers analyzed the animals’ immune response and found that when devices with adhesive coatings were first implanted, immune cells such as neutrophils began to infiltrate the area. However, the attacks quickly disappeared before scar tissue could form.
“With bonded devices, there is an acute inflammatory response because it is a foreign material,” Yuk says. “However, very quickly that inflammatory response declined and then, from that moment on, you no longer have this fibrosis formation.”
One application for this adhesive could be coatings for epicardial pacemakers, devices placed in the heart to help control heart rate. Leads that come into contact with the heart often become fibrotic, but the MIT team found that when they implanted adhesive-coated leads in rats, they remained functional for at least three months, without scar tissue formation.
Mechanical signs
The researchers also tested a hydrogel adhesive that includes chitosan, a natural polysaccharide, and found that this adhesive also eliminated fibrosis in animal studies. However, two commercially available tissue adhesives they tested did not show this antifibrotic effect because the commercially available adhesives eventually detached from the tissue and allowed the immune system to attack.
In another experiment, the researchers coated implants with hydrogel adhesives but then immersed them in a solution that removed the adhesive properties of the polymers, while maintaining their overall chemical structure. After being implanted into the body, where they were held in place by sutures, fibrotic scars occurred. This suggests that there is something about the mechanical interaction between the adhesive and the tissue that prevents the immune system from attacking, the researchers say.
“Previous research in immunology has focused on chemistry and biochemistry, but mechanics and physics can play equivalent roles, and we need to pay attention to those mechanical and physical cues in immune responses,” says Zhao, who now plans to research in more depth how these mechanical signals work. The signals affect the immune system.
Yuk, Zhao and others have founded a company called SanaHeal, which is now working on developing tissue adhesives for medical applications.
“As a team, we are interested in reporting this to the community and generating speculation and imagination about where it can go,” says Yuk. “There are many scenarios where people want to interact with foreign or artificial material in the body, such as implantable devices, drug reservoirs, or cell reservoirs.”
The research was funded by the National Institutes of Health and the National Science Foundation.