Credit: AABME (Alliance of Advanced Biomedical Engineering)
A surgical glue made with a naturally elastic protein is stronger than some currently commercially available materials and flexible enough to seal punctured lungs in animals without any sutures or mechanical bindings.
Surgeons typically reconnect tissue and seal wounds with staples, sutures, or wires. But these methods are not ideal because they puncture the tissue. This increases the risk of infection and allows fluids to leak from the closed wound.
Sealing wounds with a combination of sutures (or other mechanical methods) and surgical glue can reduce infections and prevent blood loss by filling those punctures. Glue can also seal rips, tears, and punctures in delicate tissues such as arteries or lungs. The glue, however, needs to match the natural flexibility of tissues that expand and contract. It also needs to withstand the pressure from blood flowing through blood vessels or from air filling lungs.
Current surgical glues made from cyanoacrylate polymers (the main component of Super Glue) are strong enough to hold tissue together but degrade into toxic products. Glues made with natural materials such as fibrin, a protein that helps form blood clots, are more stretchy and biocompatible, but they form weaker bonds with tissue.
This mismatch of flexibility, tissue adhesion, and biocompatibility means surgeons still use cyanoacrylates with sutures or staples, said Ali Khademhosseini, a professor at Harvard-MIT Division of Health Sciences and Technology and a lab director at Harvard’s Wyss Institute for Biologically Inspired Engineering.
A rubbery hydrogel
Over the past few years, Khademhosseini and his colleagues have developed a rubbery hydrogel, a water-absorbent network of polymer chains, made from artificially produced (recombinant) human elastin, a protein found in many stretchy tissues. After learning about the need for surgical glues during lung surgery, the researchers wondered if they could adapt this material for that role.
To make the hydrogel, the researchers first reacted the recombinant elastin with methacrylate anhydride to produce proteins with dangling methacryloyl groups. Next, they shined ultraviolet light on a solution of the protein, triggering the dangling groups to react with each other and form crosslinks between the proteins.
The researchers varied the stretchiness and flexibility of the resulting hydrogel by varying the amount of methacryloyl groups covering the protein’s surface. Additional methacryloyl groups created a stiffer material because they formed more crosslinks, creating a denser network of connections that constrain the movement of the proteins.
The researchers next examined the mechanical properties of each hydrogel, using the standard ASTM tests for lap shear, burst pressure, and wound sealing. In the lap shear test, they used the elastin glue to connect two gelatin-coated microscope slides, then measured the amount of force needed to pull the slides apart.
In the burst pressure test, the researchers punctured a collagen sheet, filled the hole with the elastin glue, pressurized the area underneath the sheet with air, and measured the amount of pressure needed for air to burst through the hole.
The wound sealing test
Finally, in the wound sealing test, the researchers applied the glue on sliced rat arteries and pig skin. Then they pulled the tissue apart and measured the amount of force needed to reopen the wound. This force represented the adhesive strength of the glue to tissue.
In the burst pressure and wound sealing tests, the elastin glue with the highest percentage of methacryloyl groups had significantly higher adhesive strength and burst pressure than two of the three commercially available bio-based surgical glues tested. The third commercial glue they tested had comparable adhesive strength but lower burst pressure.
Next the researchers tested how well the elastin-based glue sealed wounds in living animals. They sliced the lung of anesthetized rats and sealed the wound with the best-performing elastin glue. The animal survived wounds that would have ordinarily killed them. The team had similar success sealing wounds in pig lungs using only the elastin glue and no sutures.
When the researchers looked at the junction between the glue and the lung tissue under a microscope two weeks later, they saw a seamless interface. As soon as the glue contacted tissue, the hydrogel became a viscous liquid that filled the cracks and crevices of the tissue without running and dripping away before being cured with light. It is also easily applied with a syringe or a spray, Khademhosseini said.
The researchers are currently working to tailor how quickly the elastin-based glue biodegrades. Some applications may need a strong, slowly degrading glue, while others could use a glue with weaker adhesive strength and faster biodegradability. The team envisions applications ranging from treating serious internal wounds at accident sites and war zones to improving surgeries in hospitals.
The idea of chemically modifying natural protein to improve its performance interests Khademhosseini and a growing number of biomedical engineers. In the past, Khademhosseini had chemically modified gelatin and used the material as a fibrous scaffold for tissue engineering, ink for 3D printing biological materials and as a support for various organs-on-a-chip.
The advantage of chemically modifying natural proteins is that natural materials are biocompatible, naturally flexible, and inherently able to bind cells. “Then, using chemistry, we can add groups to get desired mechanical properties,” he said. “The idea is to get the best of both worlds.”
