closure and healing, though. From the sticky feet of gecko lizards to the gluey secretions of marine mollusks, evolution has provided a number of design options that might help wound healing.
Current methods simply will need improving, say physicians. “If you look at suturing, it’s almost like you’re causing trauma,” notes James Quinn, an emergency medicine doctor who studies traditional tissue adhesives at the Stanford University School of Medicine in California. “If you could patch and glue a spleen, say, or kidney together it could be incredibly useful.”
A stitch in timeThere’s something to be said for any medical procedure that has truly stood the test of time. The technique of closing wounds with needles and thread dates back at least 5,000 years to the ancient Egyptians. Even metal staples have been around in the operating room for more than a century. Yet, although sutures and staples do a good job of closing wounds, the presence of these foreign materials greatly increases the risk of inflammation and related infection. What’s more, these systems can be painful to apply, often leave behind unattractive scarring, aren’t applicable to all tissue types and are sometimes
saw-tooth edges on a serrated blade: just as a tomato is much easier to cut with a serrated knife than a plain-edged one because the strain is localized at the tips of the teeth of the blade, so too can the barbs on a quill provide cleaner cuts with lower input force and minimal tissue deformation. “Somehow, nature has evolved so that these quills present some sort of optimized force balance on the tissues,” Karp says.
Moving beyond the natural quill, Karp and his team have fabricated an artificial version of the porcupine spine out of polyurethane. And, by combining many such quill-inspired plastic needles together, they created a ‘patch’ that penetrates with reduced force, but, because the barbs snag the tissue on the way out, requires 30 times more energy to remove than a barbless model. If they can now create a biodegradable version of the design, the researchers hope to develop a commercial product that could replace surgical staples or hernia mesh tacks, among other medical applications. “This is now a new approach to creating an adhesive patch that can stick to tissue without requiring significant application force,” Karp says.
It’s not the only so-called ‘biomimetic’ adhesive that is being advanced for wound
James Ankrum is poking chicken flesh with a porcupine quill. “You can use it like a toothpick,” says the six-foot-five-inch graduate student as he lifts the tissue right off the lab bench up to his towering eye level. The dried-out cube of meat dangles in the air, held up by nothing more than the two-inch-long quill in his hand.
Ankrum may be a PhD student at the famously geeky Massachusetts Institute of Technology in Cambridge, Massachusetts, but this is not just a nerd’s idea of an exotic cocktail party trick. Together with postdoctoral fellow Woo Kyung Cho and tissue engineer Jeffrey Karp, Ankrum is taking advantage of the natural geometry of these specialized porcupine hairs to develop the next generation of medical adhesives. As they reported this past December, the microscopic, backward-facing barbs found along the tips of the North American porcupine quills help reduce the force required for these spines to burrow into tissue by more than a half compared with a barbless quill—all while causing less damage to the surrounding tissue1.
“It’s a highly engineered system,” says Karp, who co-directs the Center for Regenerative Therapeutics at the Brigham and Women’s Hospital in Boston. He likens the barbs to the
Stitches offer a suitable means of sealing up simple wounds. But when it comes to suturing tissues inside the body, the existing methods for closing wounds fall short. Elie Dolgin meets scientists taking inspiration from nature to develop the next generation of surgical adhesives.
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layer of glue10. He is currently updating the design to increase the tape’s strength. “It’s a beautiful, brilliant idea,” says Antonio Lauto, a biomedical engineer at the University of Western Sydney in Australia. “To modify the surface of the adhesive on a nanoscale so that it has the van der Waals forces to make the bonding stronger is really clever.”
Karp’s latest inspiration is Pomphorhynchus laevis. This tiny fish parasite, known as the spiny-headed worm, can grow up to 1 inch long and has a bulb at the base of its elongated nose that swells with water to secure the worm firmly in the intestinal wall of its host. Together with postdoc Seung Yun Yang, Karp has now molded an expandable proboscis-like microneedle out of polystyrene. When fashioned into a 100-needle array, this worm-inspired patch sticks to pig skin with around four times the strength of a metal staple.
“The nice thing about many of our designs is that we’ve used materials that exist in FDA-approved products,” Karp says. “So there’s opportunity now to potentially translate something like this really quickly to the clinic.”
Getting products to market drives all of Karp’s research. From the outside, it might look like he jumps from one biologically inspired project to the next with little focus on real-world application. But just as variation allows animals to adapt in nature in the face of changing environments, keeping a number of projects up and running remains Karp’s best strategy to ensure something gets to patients in an uncertain commercial landscape.
“There are so many unmet medical needs requiring better tissue adhesion, and you never truly know what’s going to work,” he says. “So, until you start moving full steam ahead on commercial development, it’s always a good idea to have two or three different strategies on the go.” It’s the kind of diversification that Darwin himself would be proud of.
Elie Dolgin is a news editor with Nature Medicine in Cambridge, Massachusetts.
1. Cho, W.K. et al. Proc. Natl. Acad. Sci. USA 109, 21289–21294 (2012).
8. Mann, L.K. et al. Acta Biomater. 8, 2160–2165 (2012).9. Haller, C.M. et al. Acta Biomater. 8, 4365–4370
(2012).10. Mahdavi, A. et al. Proc. Natl. Acad. Sci. USA 105,
2307–2312 (2008).
secretions of the sandcastle worm6, which uses its secretions to build tube reefs that somewhat resemble sandcastles, hence the name. The sandcastle worm biomimetic adhesive is moving along, with animal data showing that the glue can hold together bone fragments in rats with craniofacial defects7 and results from donated human tissue showing it can mend ruptures to the membrane that protects babies in utero8, a major complication of prenatal surgery. (Messersmith published similar data last year demonstrating fetal membrane repair with his group’s mussel-mimetic tissue adhesive9.)
The Utah team, together with colleagues at the University of Texas Health Science Center at Houston, is now testing the glue in a live pig model of preterm fetal surgery. “A lot of things have been tried to patch that hole [in the fetal membrane] after surgery, but nothing’s been shown to work,” says Russell Stewart, a bioengineer at the University of Utah who is leading the research. “We have an adhesive that we can deliver underwater in fluid that sticks to tissue and will cure. So, we’re hoping that we can solve that problem—and if it works for that, there are a lot of other medical or surgical conditions that could be treated in a similar way.”
A patch-up jobKarp, for his part, is also working on new types of glue that work under wet conditions. At last year’s American Heart Association meeting in Los Angeles, he and his colleagues reported that a polymer hardened by ultraviolet light could bind cardiac tissue and seal holes in still-beating rat and pig hearts.
But as much as he’s stuck on glue, Karp is also pushing ahead on nature-inspired needles, patches and medical tapes. In 2008, Karp’s team developed a biodegradable bandage modeled on the nanoscale topography of a gecko’s foot. Those tiny hills and valleys help the lizards cling to walls and ceilings, and by molding that same nanoarchitecture Karp produced a surgical tape that could stick to internal organs when combined with an ultrathin
difficult to administer internally during minimally invasive procedures.
Tissue glues made their debut in the 1940s when doctors first used formulations of the blood clotting protein fibrin to anchor skin grafts. By the time of the Vietnam War, medics were sealing battle wounds with the all-purpose ‘Super Glue’, made from the chemical cyanoacrylate. However, the bond strength of fibrin glue is too low for many wound-closing applications, and the toxic byproducts of cyanoacrylate breakdown, such as formaldehyde, have limited their clinical use to external applications. “The current situation really leaves a lot of room for new strategies for medical adhesion and sealing,” says Phillip Messersmith, a biomedical engineer at Northwestern University in Evanston, Illinois. “That’s why we think there are opportunities for biologically inspired approaches.”
According to Jonathan Wilker, a chemist at Purdue University in West Lafayette, Indiana, an ideal surgical glue should meet three basic criteria. It should bond tissues strongly, it should be nontoxic and it should work in wet environments like those found inside the body. Unfortunately, “there isn’t really anything out there that can do all three of those,” Wilker says. “You can pick two, and that’s easy, but getting all three is really pretty tricky.”
Both Wilker and Messersmith are independently developing adhesives inspired by the natural glues that marine mussels secrete to fasten themselves to rocks and ship hulls. The shellfish anchor incorporates a unique and rare amino acid called 3,4-dihydroxyphenylalanine (DOPA), a derivative of tyrosine that effectively ‘cures’ the mussel secretion by crosslinking matrix proteins. Wilker’s and Messersmith’s products both use a variant of DOPA called catechol for added strength. But, instead of crosslinking proteins as the base material, their glues use catechol to crosslink medical-grade plastic polymers—polystyrene in the case of Wilker’s glue2 and polyethylene glycol for the one that Messersmith is working on3.
“Our approach is to say, let’s chemically synthesize the same functional group found in DOPA that’s responsible for adhesion and incorporate that chemically into a biocompatible polymer,” explains Messersmith. Both products are far from the clinic, although Messersmith has shown that his glue helps anchor tissue grafts of islet cells in a mouse model of diabetes4.
Additional inspiration has come from mussels’ underwater companions. A team from the Marine Biotechnology Institute in Japan has synthesized an adhesive peptide inspired by the one secreted by barnacles5, and researchers at the University of Utah in Salt Lake City have advanced a surgical glue modeled after the sticky
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“There are so many unmet medical needs requiring better
