Inspired by the sticky substance that barnacles use to cling to rocks and other surfaces, Massachusetts Institute of Technology (MIT) engineers have designed a strong, biocompatible glue that can seal injured tissues and stop bleeding. The new paste can adhere to surfaces even when they are covered with blood, and form a tight seal within about 15 seconds of application. The researchers suggest that such a glue could offer a much more effective way to treat traumatic injuries and help to control bleeding during surgery.
“We are solving an adhesion problem in a challenging environment, which is this wet, dynamic environment of human tissues,” said Xuanhe Zhao, PhD, a professor of mechanical engineering and civil and environmental engineering at MIT and one of the senior authors of the study, which is published in Nature Biomedical Engineering. “At the same time, we are trying to translate this fundamental knowledge into real products that can save lives.” Zhao and colleagues describe development of the new surgical glue in a paper titled, “Rapid and coagulation-independent haemostatic sealing by a paste inspired by barnacle glue.” Co-senior author of the paper is Christoph Nabzdyk, MD, a cardiac anesthesiologist and critical care physician at the Mayo Clinic. Co-lead authors are MIT research scientist Hyunwoo Yuk, PhD and postdoc Jingjing Wu, PhD, in Rochester.
Tissue and organ-related hemorrhages can be life threatening, and are challenging to treat, owing to the highly time-sensitive and often complex nature of the injury, the authors noted. In fact, uncontrolled hemorrhages are one of the major causes of mortality in the world, accounting for more than two million deaths annually. Among members of the military, blood loss is the leading cause of death following a traumatic injury, and among the general population, it is the second leading cause of death following a traumatic injury.
Sutures are commonly used to seal wounds, but putting stitches in place is a time-consuming process that usually isn’t possible for first responders to perform during an emergency situation. In recent years, some materials that can halt bleeding, also called hemostatic agents, have become commercially available. Many of these consist of patches that contain clotting factors, which help blood to clot on its own. “Existing topical hemostatic agents mostly aim to augment and accelerate intrinsic blood coagulation to enable hemostasis,” the team explained. “The majority of FDA-approved hemostatic products rely on the formation of blood clots for hemostatic sealing of bleeding injuries by the use of coagulation-promoting materials (for example, gelatin, collagen, oxidized cellulose) and/or concentrated coagulation factors (for example, fibrin, thrombin).”
However, these products do require several minutes to form a seal and don’t always work on wounds that are bleeding profusely. “ … the inherently gradual nature of blood-clot formation limits the speed of hemostasis and cannot offer rapid hemorrhage control,” the scientists continued. “Additionally, rapid or pressurized blood flow through a wound bed can wash out any forming blood clot, potentially limiting the efficacy of coagulation-dependent hemostasis.”
An alternative to boosting blood clotting is physically sealing bleeding tissues using adhesives, and this offers what the team suggests is “… a promising alternative to blood coagulation to achieve hemostasis.” However, they pointed out, tissue adhesives do not normally work well on tissues that are covered with blood or other bodily fluids. “Although a few blood-resistant tissue adhesives with improved adhesion performance have been developed, the need for ultraviolet (UV) irradiation and/or the prolonged application of steady pressure (for example, more than 3 min) to form adhesion substantially limits their utility for clinical applications.”
Zhao’s lab has been working to address the problem for several years. In 2019, his team developed a double-sided tissue tape and showed that it could be used to close surgical incisions. This tape, inspired by the sticky material that spiders use to capture their prey in wet conditions, includes charged polysaccharides that can absorb water from a surface almost instantaneously, clearing off a small dry patch that the glue can adhere to.
For their newly developed tissue glue, the researchers this time turned their attention to the barnacle, a small crustacean that attaches itself to rocks, ship hulls, and even other animals such as whales. These surfaces are wet and often dirty—conditions that make adhesion difficult.
“This caught our eye,” Yuk said. “It’s very interesting because to seal bleeding tissues, you have to fight with not only wetness but also the contamination from this outcoming blood. We found that this creature living in a marine environment is doing exactly the same thing that we have to do to deal with complicated bleeding issues.”
The researchers’ analysis of barnacle glue revealed that it has a unique composition. The sticky protein molecules that help barnacles attach to surfaces are suspended in an oil that repels water and any contaminants found on the surface, allowing the adhesive proteins to attach firmly to the surface. “The lipid-rich matrix of the barnacle glues first cleans the underlying substrate by repelling water and contaminants, and subsequently the adhesive proteins crosslink with the substrate to form stable and strong adhesion,” they commented. “Although the adhesive proteins of the barnacle glues have been investigated and synthesized to develop underwater and tissue adhesives, the aforementioned mechanism—which is based on the synergistic interplay between the lipid-rich matrix and adhesive proteins in the barnacle glues—has remained unexplored for tissue adhesives.”
The MIT team decided to try to mimic this glue by adapting an adhesive they had previously developed. This sticky material consists of a polymer called poly(acrylic acid) embedded with an organic compound called an NHS ester, which provides adhesion, and chitosan, a sugar that strengthens the material. The researchers froze sheets of this material, ground it into microparticles, and then suspended those particles in medical-grade silicone oil. “The bioadhesive takes the form of an injectable paste that consists of a hydrophobic oil matrix and bioadhesive microparticles, which take on similar functional roles to the lipid-rich matrix and the adhesive proteins in barnacle glues, respectively,” the investigators wrote.
They showed that when the resulting bioadhesive paste is applied to a wet surface such as blood-covered tissue, the oil repels the blood and other substances that may be present, allowing the adhesive microparticles to crosslink and form a tight seal over the wound. Tests in rats showed that the glue sets and bleeding stops within 15 to 30 seconds of application, when gentle pressure is applied.
One advantage of this new material over the double-sided tape is that the paste can be molded to fit irregular wounds. The tape might be better suited to sealing surgical incisions or attaching medical devices to tissues, the researchers suggested. “The moldable paste can flow in and fit any irregular shape and seal it,” Wu commented. “This gives freedom to the users to adapt it to irregular-shaped bleeding wounds of all kinds.”
Through further tests in pigs, Nabzdyk and his colleagues at the Mayo Clinic found that the new glue was able to rapidly stop bleeding in the liver, and worked much faster and more effectively than the commercially available hemostatic agents they tested in comparison. The glue paste even worked when strong blood thinners (heparin) were given to the pigs so that the blood did not form clots spontaneously. “The paste may aid the treatment of severe bleeding, even in individuals with coagulopathies,” the authors noted.
Encouragingly, the studies showed that the seal remained intact for several weeks, giving the tissue below time to heal itself, and that the glue itself induced little inflammation, similar to that produced by currently used hemostatic agents. The barnacle-inspired adhesive paste is slowly resorbed within the body over months, but can also be removed earlier by applying a solution that dissolves it, if necessary. “Our data show how the paste achieves rapid hemostasis in a coagulation-independent fashion,” added Nabzdyk. “The resulting tissue seal can withstand even high arterial pressures. We think the paste may be useful in stemming severe bleeding, including in internal organs, and in patients with clotting disorders or on blood thinners. This might become useful for the care of military and civilian trauma victims.”
The researchers now plan to test their glue on larger wounds, and hope the results will demonstrate that the adhesive would be useful to treat traumatic injuries. They also envision that it could be useful during surgical procedures, which often require surgeons to spend a great deal of time controlling bleeding. “We’re technically capable of carrying out a lot of complicated surgeries, but we haven’t really advanced as fast in the ability to control especially severe bleeding expeditiously,” Nabzdyk said.
Another possible application would be to help stop bleeding that occurs in patients who have plastic tubes inserted into their blood vessels, such as those used for arterial or central venous catheters or for extracorporeal membrane oxygenation (ECMO). During ECMO, a machine is used to pump the patient’s blood outside of the body to oxygenate it. It is used to treat people with profound heart or lung failure. Tubes often remain inserted for weeks or months, and bleeding at the sites of insertion can lead to infection.
The team acknowledged that further research will be needed to validate the effectiveness and potential of the barnacle-glue-inspired adhesive paste in clinical applications. “… clinical translation and potential regulatory approval of the barnacle-glue-inspired paste for specific indications in human use will require further investigations and optimization in terms of adhesion performance, application process, and swelling ratio,” they noted. Nevertheless, the scientists concluded, while it is still in early stages of development, the barnacle-glue-inspired paste offers “a promising option” for achieving rapid control of severe bleeding, even in the presence of clotting disorders, where commercial haemostatic agents aren’t effective.
“The in vivo rodent and porcine models validate the efficacy of the barnacle-glue-inspired paste as a promising hemostatic agent to achieve rapid, robust and coagulation-independent haemostatic tissue sealing, superior to that of widely adopted, FDA-approved, commercially available hemostatic agents ….” They say that they envision that the barnacle-glue-inspired paste will not only provide an effective tool for rapid and coagulation-independent hemostasis, wound closure, and surgical repair, but will also offer valuable insights for the future design and development of adhesives for use in wet and contaminated environments.
