Web of Intrigue the Sturdy, Stretchy, Sticky Silks Spun by Spiders Have Inspired Engineers to Design Pioneering Medical Devices Such As Artificial Tendons and Corneas

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OUTLOOK BIOMATERIALS LEFT: MENA KLITTICH, DHARAMDEEP JAIN & ALI DHINOJWALA/UNIV. AKRON; RIGHT: MICHAEL ABBEY/SPL AKRON; RIGHT: & ALI DHINOJWALA/UNIV. MENA KLITTICH, DHARAMDEEP JAIN LEFT:

A synthetic mimic (left) of natural spider silk (right) incorporates polymer drops that can be used as a drug-delivery system.

SPIDERS Web of intrigue The sturdy, stretchy, sticky silks spun by spiders have inspired engineers to design pioneering medical devices such as artificial tendons and corneas.

BY KATHERINE BOURZAC these natural fibres have attracted the attention Medford, Massachusetts. “There’s clearly a need of materials scientists. Researchers are looking for new biomaterials,” he says. For Kaplan and Madagascan bark spider releases a silk to arachnids and other silk makers for ideas others, silk is the best way to meet that need. dragline into the air. The wind carries about how to make new structural materials for the thin threads to the other side of a bridges and vehicles, dirt-resistant adhesives COMMON THREAD Ariver, where they land on foliage on the oppo- for climbing robots and sturdy polymers for Silk evolved independently in many inverte- site bank 25 metres away. The spider (Caero- biomedical devices. Many silks bring together brates, including spiders, honeybees and silk- stris darwini) then stretches the bridgeline to properties that are not readily present in man- worms. Individual spiders can make as many establish tension, reinforces it, and draws on made materials — the extreme toughness and as six different kinds of silk proteins (and two a palette of other silks, stretchier or stickier as elasticity seen in spider threads is one example. glue proteins), each of which has evolved over needed, to fashion a web to capture the bugs Silk proteins can be moulded like plastic or per- the creatures’ 400 million years of natural his- flying over the water1. form optical functions like silicon. Yet because tory. Each spider species uses its own varia- C. darwini’s bridging silk is the world’s they’re organic, biological materials, silks are tions of these proteins to make many different toughest known biomaterial — it is even environmentally friendly and biocompatible. types of thread. tougher than steel (see ‘The toughest thread’). Silk proteins can be fashioned into films that “We think that a primordial spider had But C. darwini’s versatility in producing differ- can be implanted in the body, releasing drugs one kind of silk, and then there were multiple ent kinds of silk is not unique. Many spiders as they dissolve. This combination of features events when the gene duplicated and evolved,” can spin several silks: stiff, structural strands is unavailable in polyester or collagen or any- says Cheryl Hayashi, a spider specialist at the to stabilize their webs; gooey, stretchy spirals to thing else, says David University of California, Riverside. The species capture flying insects; adhesive pads to anchor Kaplan, an early pro- NATURE.COM that are more closely related to these ancestors, their homes in place; and extraordinarily robust ponent of high-tech Read about spider such as tarantulas and trapdoor spiders, make draglines from which to hang. biomedical silk at genomes at: silks of simple designs — messy tangles to trap The remarkable mechanical properties of Tufts University in go.nature.com/jwvsc4 walking insects, for example, using fewer types

of silk. Other spiders evolved to make more complex spiralling orb webs, in which different regions are composed of different kinds of silk — some optimized for capturing prey, oth-

RANDOLPH V. LEWIS RANDOLPH V. ers for structural support of large web designs. This evolutionary bounty has happy impli- cations for engineers looking to put spider silk into human service. If a design calls for a fibre with a particular ratio of strength to stretchi- ness, “it’s probably already been invented” by one of the tens of thousands of types of spider, says Hayashi. Most research has centred on taking advantage of the toughness of spider silk — in materials science, toughness is a measure of how much energy it takes to break something. Materials such as spider silk are both strong and elastic. A large insect that flies into a spi- derweb at top speed stretches the superfine fibres in the web but does not break them. The toughest silks are found in spider draglines, which researchers are studying Artificial silk is spun from genetically engineered spider-silk proteins at Utah State University in Logan. intensely. Spiders use draglines to dangle safely, to make the frames of their webs, and that is also known as the golden silk orb- is continuing to work on producing proteins for situations in which resistance to breakage weaver. Since then, Lewis and others have two to three times that size, much closer to is paramount. In a scene from the 2004 movie succeeded in expressing this protein in many natural spider-silk proteins, in genetically Spider-Man 2, the eponymous superhero production systems, including the bacte- modified organisms. “The tensile strength is stops a runaway New York City subway train rium Escherichia coli, alfalfa and goats, which going to improve,” he says. with his webbing, which is not too far of a express the molecule in their milk. Lewis has Even with the right proteins, humans are stretch from reality. In 2012, physics graduate started a company called Araknitek to develop at a disadvantage in putting them together students at the University of Leicester, UK, and license these proteins. because we still do not fully understand how calculated that dragline silk spun by the There are other companies developing spi- spiders do it. Artificial silk fibre-spinning Darwin’s bark spider would be able to perform der-silk proteins. AMSilk, which is based near techniques are based on the methods used a feat just as shown in the film. Munich, Germany, manufactures synthetic to make polymer fibres such as Kevlar. These If it could be manufactured, the Darwin’s spider-silk proteins techniques work well for the artificial poly- bark spider’s dragline silk would be valuable for use in cosmetics “Our best mers they were designed for but not as well for use in applications in which a lightweight, and shampoos; Spiber fibres have for proteins. The proteins are pushed out of yet very strong, material is crucial: helmets for Technologies, based in about half to the tip of a fine needle, washed in baths of fighter pilots, artificial tendons and ligaments, Stockholm, is selling two-thirds the water or alcohol, then stretched and dried or Spider-Man-like climbing ropes. But spiders meshes and films for tensile strength — a process very different from the method are, from a practical, manufacturing point growing cell cultures spiders use. Scientists know that spiders pull of view, useless. Spiders become cannibals consisting of labora- of spider silk.” silks out of dedicated glands, some of which when kept in captivity, and so must be caught tory-made spider silk. contain more than one kind of protein. The from the wild. To obtain natural spider silk, a Another almost identically named company silk emerges from the gland as a highly con- researcher must anaesthetize a spider, attach — Spiber Inc. in Tsuruoka, Japan — has spun centrated liquid solution of fibres that solidi- the end of one of its fibres to a variable-speed off from Keio University. Many commercially fies as it is pulled out. This process has not motor from an electric drill, then gently pull minded companies are developing films or yet been mimicked, and researchers are only the thread out of one of the spider’s glands. fibres of artificial spider silk for use in medi- beginning to understand the details of anat- Depending on the species of spider, this tech- cal devices and textiles. omy and physiology that make silk possible. nique can yield up to 100 metres of silk. This But no one has figured out how to produce Anna Rising, a biochemist at the Swedish painstaking process is easier than picking apart spools of silk as tough as the original. “Our University of Agricultural Sciences in Upp- the threads from spiderwebs, but it is not scal- best fibres have about half to two-thirds the sala, is turning to spiders for clues on fibre able. So researchers have been working on how tensile strength of spider silk,” says Lewis. One spinning. To learn more about how to make to generate spider silks without spiders. The problem is that engineered spider-silk protein tough silk fibres, she and a student performed process presents two initial challenges: first, molecules are not as large as the originals. A an intricate study3 that they hope will lead where to find the proteins; and second, how to general rule of fibre-spinning, whether the to insights that can be applied to industrial assemble the proteins into a useful fibre. materials are proteins or plastics, is that the silk-making. They placed microelectrodes larger the molecules, the stronger the fibre. along a living spider’s silk glands, from the FIBRE FOCUS But this trend bumps up against an axiom of bag-like reservoir down the narrowing tube To realize the dream of artificial spider silk bioengineering: the bigger the protein, the to its opening. These sensors revealed that as an engineering material, researchers more difficult it is to produce in a genetically “there’s quite an impressive pH gradient and have started with genes. Randolph Lewis, a modified organism. Natural dragline proteins an increase in CO2” along the length of the bioengineer at Utah State University in Logan, have molecular masses of 250 to 500 kilodal- gland, she says. Rising is now working on rep- sequenced2 the first spider-silk protein gene tons; genetically modified organisms made in licating these gradients, which she says prob- in 1990. Lewis chose the dragline of Nephila the laboratory produce silk proteins of only ably help to control the crystallization of the clavipes, a species indigenous to the Americas about 60 to 80 kilodaltons. Lewis says that he silk proteins as they are spun.

Rising has also found that, while inside the thread is already used extensively in medical gland, the head of one silk protein attaches to settings, where it is the most commonly used

THE TOUGHEST THREAD E11234 5, the tail of the next in such a way that groups Seemingly delicate spiderwebs are constructed suture material. And some silk biomedical 4 of them line up in a row . As the proteins are from incredibly robust silk bres that surpass devices made by Kaplan and other researchers art cial materials in toughness (the amount of 528–531 (2010).

assembled inside the gland, they pre-align. are on the market or in clinical trials for soft- ONE PLOS 329,

energy they can absorb before breaking). The better aligned the proteins are in a fibre, tissue reconstructive surgery. Furthermore, the stronger it is. This might also be mim- Orthox in Oxfordshire, UK, is testing silk

400 SCIENCE icked in synthetic fibres. Swedish company 354 devices for knee repair. Many of the research- Spiber is working to commercialize Rising’s 350 ers working on producing spider silk would ) ideas, producing recombinant silk proteins in 3 300 like to use it in similar applications, such as E. coli with the goal of making replacement 250 repairing ligaments, where its extra toughness tendons and ligaments for clinical use. 200 would be an additional bonus. Hayashi hopes more insights will come Tara Sutherland, a bioengineer at the Com- from watching the silk gland develop, as 150 111 monwealth Scientific and Industrial Research young spiders mature into adults. She is (MJ/m Toughness 100 Organization in Canberra, Australia, is look- studying Latrodectus hesperus, commonly 50 ing to silks that are less well known than those (2010); OMENETTO, F. G. & KAPLAN D. L. F. (2010); OMENETTO, called the black widow spider. This species 0 from spiders and silkworms. Sutherland’s has seven types of silk glands, each of which analysis6 has uncovered 23 groups of inde- Bone it draws on to make a unique silk fibre. pendently evolved types of silk in 100,000 dif- A. T. M. & BLACKLEDGE, I., KUNTNER, AGNARSSON, SOURCES: Although many researchers have been ferent insect species. In common with Kaplan, Nylon fibre Nylon inspired by the mechanical toughness of spi- spider bark Sutherland has medical applications in mind. Silkwormsilk der draglines, others see broader potential in fibre 49 Kevlar She zeroed in on one insect from thousands Tendon collagen Tendon High-tensile steel High-tensile spider silks. Todd Blackledge, an entomolo- spider orb-weaver of options: the honeybee. Honeybees use silk Silk ofSilk Darwin’s the gist at the University of Akron in Ohio, was ofSilk silk golden the to provide thermal insulation and structural the first to characterize the silk of Darwin’s support for their hives. bark spider. He says that focusing on just one Sutherland approached the problem of spider or one kind of silk would be like work- component, called fibroin. Kaplan sees the picking the right silk from a bioinformatics ing only with inbred white laboratory rats. He potential of fibroin — and it is not necessar- point of view, not an evolutionary one. She is looking at silks made by other spiders, and ily in the form of fibres. wanted to make the most of what biopoly- is working with Akron materials scientist Ali Silkworm fibroin is readily available and mers offer. Unlike plastics and other mate- Dhinojwala to study what makes some spi- easy to work with, says Fiorenzo Omenetto, rials, proteins can sense and respond to the derwebs sticky. The pair have found that, for a Tufts biomedical engineer with exper- environment. Sutherland wants to make many silks, stickiness comes not only from tise in photonic materials. To compete with tissue-engineering scaffolds that release cell- chemistry but also from architecture. commodity materials such attracting signals on cue, or silk bandages that One common arachnid adhesive tech- as plastics and silicon for “Silk is the release antibiotics when they sense an infec- nique is to make a patch of tightly packed, applications in electronics tion. She has funding from the clothing firm parallel silk threads to secure the dragline and medical devices, scale is best stuff Nike and NASA, among others. at one end. Spiders do this so that they may key. Omenetto orders huge on Earth. Seeking a silk that would be easy to modify safely dangle. The adhesive patch is made of boxes of silkworm cocoons, There’s to add smart features, her analysis pointed parallel threads of a coil-shaped silk protein then processes them accord- nothing to the type produced by honeybees. These called pyriform silk; fibres made from this ing to a recipe originally like it.” proteins are smaller than those found in spi- protein are highly elastic, like a rubber band. developed by Kaplan. The der silks and so are easier to genetically engi- The pyriform silk is coated with a sticky pro- cocoons are cut open and the pupae removed. neer. Sutherland’s analysis showed that huge tein solution. Removal of this kind of dense Then the cocoons are put into a hot bath to stretches of the genetic sequence could be adhesive patch requires pulling hundreds of wash the silk fibres clean of the gluey glyco- altered without interfering with the proteins’ elastic silk strands past their breaking point. protein sericin, before being processed to dis- toughness and biodegradability. That gives her Dhinojwala, a polymer chemist, mimicked solve and purify the fibroin protein. more room to engineer in new functions, such this in a polymer adhesive patch. He showed The thick, water-based solution that results as attracting cells to help rebuild tissue. Suther- that a patch of polymer threads with the right can be mixed with drugs or other biomol- land is now developing bioactive bandages and elasticity is sticky like the spider patches and ecules or nanoparticles, then moulded into other medical devices that use these silks. hopes to develop artificial patches for use in films or other structures. By controlling the For Sutherland and others, the fibres pro- surgical repair of tendons. conditions during the drying step, researchers duced by silk makers in the wild are endlessly can direct the crystallization of fibroin into fascinating and full of design ideas. “Silk is BEYOND SPIDERS forms that will dissolve on a desired timescale the best stuff on Earth,” says Kaplan. “There’s Whereas some researchers have been untan- inside the body. nothing like it.” ■ gling the challenges of spider silks, others Kaplan and Omenetto have made silk films have been taking advantage of the properties to house biodegradable electronic devices Katherine Bourzac is a freelance science of silks made by an animal that is easier to that monitor heart function and then dis- writer in San Francisco, California. 5 work with. The silkworm, Bombyx mori, has solve . They have also made drug-releasing 1. Gregorič, M., Agnarsson, I., Blackledge, T. A. & long been domesticated for the production of implants, artificial corneas, silk orthopaedic Kuntner, M. PLoS ONE 6, e26847 (2011). 2. Xu, M. & Lewis, R. V. Proc. Natl Acad. Sci. USA 87, lustrous textiles. hardware strong enough to screw into bone 7120–7124 (1990). Silkworm fibre is not as tough as spi- and then degrade over time, and squishy 3. Andersson, M. et al. PLoS Biol. 12, e1001921 (2014). ders’ silks and is in many ways simpler. The scaffolds for growing neurons from the brain’s 4. Kronqvist, N. et al. Nature Commun. 5, 3254 (2014). 5. Tao, H. et al. Proc. Natl Acad. Sci. USA 111, insects do only one thing with their silks: cerebral cortex. 17385–17389 (2014). build cocoons for shelter during metamor- Medical applications are paving the way for 6. Sutherland, T. D., Young, J. H., Weisman, S., Hayashi, C. Y. phosis. And their silk has just one structural technological uses of silk, says Kaplan. Silk & Merritt, D. J. Annu. Rev. Entomol. 55, 171–188 (2010).