Finding a great glue is a sticky task — especially if you want it to attach to something as slick as the inside of the human body. Even the strongest human-made adhesives don’t work well on wet surfaces like tissues and organs. For surgeons closing internal incisions, that’s more than an annoyance. The right glue could hold wounds together as effectively as stitches and staples with less damage to the surrounding soft tissue, enabling safer surgical procedures.
A solution might be found under wet leaves on a forest floor, recent research suggests. Jianyu Li of McGill University in Montreal and colleagues have created a surgical glue that mimics the chemical recipe of goopy slime that slugs exude when they’re startled. The adhesive stuck to a pig heart even when the surface was coated in blood, the team reported in the July 28 Science. Using the glue to plug a hole in the pig heart worked so well that the heart still held in liquid after being inflated and deflated tens of thousands of times. Li, who did the research while at Harvard University, and colleagues also tested the glue in live rats with liver lacerations. It stopped the rats’ bleeding, and the animals didn’t appear to suffer any bad reaction from the adhesive.The glue has “excellent, excellent properties,” says Andrew Smith, a biologist at Ithaca College in New York.
And slugs aren’t the only biological inspiration for new adhesives. Clues to better glues have long been hiding out in damp, soggy and downright wet places. For slugs, mussels, marine worms and a cadre of other critters, secreting sticky substances that attach strongly to soaked surfaces is just a fact of life. That’s why scientists are studying the structures of those substances to design new and better surgical adhesives.
“There’s really a big need to develop new ways of sealing tissues, of affixing devices to tissues — in particular, for minimally invasive procedures,” says Jeff Karp, a biomedical engineer at Brigham and Women’s Hospital in Boston. While existing medical-grade superglue is great at sealing up fingertip cuts, it is too toxic to use inside the body. Other alternatives just aren’t sticky enough to fully replace stitches. With a better glue, surgeons could also make snips that are too tiny to be stitched or stapled closed. Smaller incisions speed healing time and decrease risk of complications, Karp says.
Smith says he isn’t surprised that slug slime could lead to a big advance. For several years, he’s been trying to understand how the slug Arion subfuscus builds its ooze. For his research, Smith prods slugs gently with the tip of a metal spatula to startle them, and scoops up the slime as it’s released. “If you get it on your hands, it’ll set within seconds into an extremely sticky material,” he says.
The goo, Smith and others have found, overcomes a major challenge that adhesive designers face. It seems obvious that glue should be sticky. Yet the molecules in glue need to adhere not just to the things you’re trying to stick together, but also to each other. And that stickiness can’t come at the expense of flexibility, especially for medical applications. Soft, squishy organs are going to jiggle; skin is going to stretch. Without some bendiness, the glue might attach securely to each of the surfaces being stuck together, but the glob of glue itself might snap or shear under stress.
Slug defense slime solves that problem with two interwoven networks of molecules, tangled together like strings of holiday lights. One network is rigid, with chemical bonds that break easily, Smith says. The other is deformable, stretching substantially without breaking. This combo makes the goo simultaneously tough, flexible and sticky.
Li’s slug-inspired adhesive takes a similar approach. One layer of the material is a polymer, a type of material made from long molecules built from many repeated subunits, like a string of beads. Positively charged appendages dangling off the polymers are drawn to wet tissue surfaces by the same forces underlying static electricity. This first layer weaves into another layer, a water-based gel. The gel layer acts like a shock absorber in a car, Li says. It soaks up energy that might otherwise dislodge or snap the adhesive.
Despite being 90 percent water, the material is both sticky and tough, Li says. The fact that it’s mostly water makes it more likely to be nontoxic to humans.
STICK TEST Researchers put an adhesive inspired by the chemical structure of slug slime through its paces. The glue stayed firmly attached even when stretched, for example, and was able to cling to the slippery surface of a bloody pig heart. J. Li et al/Science 2017
Though Li’s adhesive has been tested only in human cell cultures and in lab animals, another bio-inspired glue has made its way into human trials. It’s based on work published by Karp and colleagues in 2014 in Science Translational Medicine. Karp’s team developed a viscous liquid that solidifies into a tough but stretchy glue when illuminated by light, and demonstrated that the liquid can seal holes in hearts.
“Nothing we create is really that similar to anything you see in nature, but some of the ideas gave us critical insights,” Karp says. The researchers realized, for example, that a lot of natural glues that work in water have hydrophobic elements that help clear away the water for a better stick. The research sparked Karp and colleagues to found a company, Gecko Biomedical, which Karp now advises. On September 11, the company announced the completion of a small clinical trial of its adhesive: The sealant immediately stopped blood flow after an artery-clearing operation in about 85 percent of 22 participants. Because of that success, Gecko Biomedical now has approval to market the glue in Europe.
Bio-inspired adhesives can do more than patch up incisions, though. Russell Stewart, a bioengineer at the University of Utah in Salt Lake City, is tapping into marine-dwelling sandcastle worms for a different glue goal: He wants to create a better embolic agent — a way to deliberately block blood flow to certain tissues. Embolic agents can cut blood flow to a tumor, say, or stem internal bleeding. Often, these materials are liquids that reach their target through a catheter and then solidify into a sticky mass to block tiny vessels. But such glues can be difficult to control — they need to harden at just the right time and current options often rely on harsh materials that require special equipment and can cause pain for patients.
Inspired by the sandcastle worm (Phragmatopoma californica), Stewart has designed a new — and he thinks better — embolic agent. A sandcastle worm uses fingerlike appendages coming out of its face to arrange grains of sand into expansive tubular reefs. It squirts small dabs of a liquid adhesive out of these appendages to make the grains stick together. That glue’s structure is quite different from slug slime, Stewart has found. It’s a solution of oppositely charged proteins strongly attracted to each other. The proteins make up a dense liquid that doesn’t mix with water. A worm packages each ingredient in the glue separately, so the proteins combine only once secreted. After mixing, the glue solidifies in about 30 seconds.
Stewart’s mimic also starts out as a liquid that transforms into a hard foamlike material within a few seconds of hitting blood, his team reported in 2016 in Advanced Healthcare Materials. That means the material can be injected as a liquid and doesn’t harden until it’s in the right place. Early tests have been promising: The foam completely blocked the arteries of rabbits’ kidneys without moving into tissue where it didn’t belong.
The range of biological adhesives is impressive, says Jonathan Wilker, a chemist at Purdue University in West LaFayette, Ind. “They’re so wildly different,” both in terms of chemical makeup and functional properties. That diversity provides a wide palette for scientists seeking glues for specialized applications. And Wilker’s own work adds mussels to the list.
Mussels secrete a strong adhesive that helps them stick tenaciously to rocks and ship hulls. Their secret is a molecule called DOPA, Wilker says. DOPA, or 3,4-dihydroxyphenylalanine, sticks well to other DOPA molecules and to other substances. That gives it the same balance of toughness and stickiness that’s also found in slug slime. Certain amino acids found in mussel proteins might also aid the underwater adhesion. For example, an amino acid called lysine that hangs off of mussel adhesion proteins appears to help clear water molecules out of the way, leaving a drier surface for proteins glomming on.
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Wilker’s copycat adhesive is made up of long chains of polystyrene molecules (essentially, Styrofoam) with units of DOPA mixed in. Those long chains of tricked-out polystyrene molecules tangle together and cross-link to create a strong adhesive. He’s made different varieties of the mimic, tailored for different applications. After being immersed in water, one version held on tighter underwater than the glue made by mussels themselves, Wilker’s team reported in February in Applied Materials Interfaces. Another version is biodegradable.
If he can make the glues nontoxic to cells, they could possibly be used inside the body. In one recent study, Wilker created an artificial adhesive protein that mimics the natural protein elastin. The artificial version excelled in both dry and damp test environments, his team reported in April in Biomaterials.
Bringing animal-inspired adhesives into the human body won’t necessarily be a simple task, though. It requires tackling some problems that other animals don’t need to solve, Karp says. A slug, for instance, produces its slime as it needs it. It doesn’t stockpile gallons of glue in its tiny body, or instantly churn out a year’s supply. A successful real-world glue, however, will need to be easy to produce in large quantities and safe to store for months at a time, Karp points out. Those are problems humans will have to solve on their own. That’s the next challenge.