Chemical & Engineering News

June 9, 1997

Copyright © 1997 by the American Chemical Society


Using solvent-swollen polymer networks that respond to stimuli, scientists
are beginning to develop a soft, wet, organic technology

Ron Dagani
C&EN Washington

"It was very puzzling," says Toyoichi Tanaka, referring to a discovery he made shortly after joining the physics faculty at Massachusetts Institute of Technology in 1975. He and his coworkers were studying gels, cross-linked polymer networks that can absorb enough solvent to swell. They discovered that by cooling a clear polyacrylamide gel, they could make it cloud up and eventually become opaque. Warming the gel restored its clarity. That was not the kind of behavior Tanaka had been expecting. What he had stumbled upon was a phase transition in a polymer network--a phenomenon akin to the interconversion of the liquid and vapor phases of water at the critical point.

Some of Tanaka's colleagues, however, were skeptical of his explanation because the gel transition occurred at about -20°C. They thought his observations might be due to the formation of tiny ice crystals in the gel. To prove them wrong, Tanaka embarked on another experiment, one involving ionized gels immersed in water-acetone solutions. He was hoping to quell the doubts by pushing the phase transition into the room-temperature range. But he ended up making an even more dramatic discovery that opened up a new field of research. In essence, Tanaka discovered that a small change in solvent concentration or temperature can cause a gel to abruptly swell to many times its original size--or collapse into a compact mass.

MIT's Tanaka shows off transparent, egg-shaped gel that responds to temperature.

Such a definitive phase transition had not been seen before in synthetic polymers, although it had been predicted in 1968. Certainly, gels that swell or contract gradually over time had been known for more than 25 years before Tanaka began his experiments. But his gels were different--they reacted to an external stimulus in a manner more reminiscent of living organisms than inanimate matter. The unique properties of these gels soon attracted other investigators, including chemists and chemical engineers, who were intrigued by the materials' potential uses in fields as far-flung as medicine and robotics.

Today, two decades after Tanaka's demonstration of the first "smart" or "intelligent" gels, these materials are just beginning to trickle into the marketplace. Behind the commercialization effort is a much larger effort--most visible in academic labs--that is aimed at gaining a better understanding of these fascinating materials and improving their properties and performance.

The most extensive investigations on stimuli-responsive polymers have been carried out on hydrogels--gels that swell in aqueous solvents. Most of that work has focused on hydrogels that respond sharply to small changes in temperature or pH. But researchers also have been probing gels that respond to changes in ionic strength, solvent, pressure, stress, light intensity, and electric or magnetic fields. Some gels also have been engineered to respond to specific chemical triggers, such as glucose.

A stimulus as subtle as a 1°C change in temperature can make some gels swell hundreds of times in volume--or collapse, expelling up to 90% of their fluid contents. Other gels don't swell, but their physical properties change. Such behavior has led to serious efforts to develop gel-based actuators, valves, sensors, controlled-release systems for drugs and other substances, artificial muscles for robotic devices, chemical memories, optical shutters, molecular separation systems, and toys. Other potential applications that have been considered include paints, coatings, adhesives, recyclable absorbents, bioreactors containing immobilized enzymes, bioassay systems, and display devices.

In 1992, recognizing that responsive-gel technology was ripe for commercialization, Tanaka and entrepreneur George W. McKinney III founded Gel Sciences in Bedford, Mass., to pursue industrial applications of the technology. Two years later, McKinney, then president of Gel Sciences, met chemist-entrepreneur Eyal S. Ron, and the two started a subsidiary called GelMed to pursue the medical applications. As time went on, the medical side of the business grew more than the industrial side. Recently, the two companies coalesced into a single entity that is, for the most part, medically oriented, says Ron, who is vice president for technology at Gel Sciences/GelMed.

Last year, the company commercialized its first product: a viscoelastic gel that is soft and pliable at room temperature but becomes much firmer when exposed to body heat. The material, dubbed SmartGel, is being used as a shoe insert--for instance, in in-line skate shoes--to make the shoe conform to the wearer's foot and provide the necessary support and comfort. SmartGel is the only responsive gel product on the market, according to Ron.

Smart Hydrogel, a product of Gel Sciences/GelMed that is in commercial development, is liquid at room temperature and viscous at body temperature at very low concentrations (1 to 3%) in water. Source: Gel Sciences/GelMed.

That distinction almost went to Cloud Gel, a material that Suntek, a company based in Albuquerque, N.M., began developing in 1980. Cloud Gel is a clear, transmissive hydrogel that becomes translucent, white, and largely reflective when it is warmed to a preset temperature or exposed to bright light. Cooling the material reverses the process. Placed between plastic or glass sheets, Cloud Gel could be used to moderate the amount of light and heat passing through skylights, greenhouse walls, and other types of windows. Despite write-ups in the New York Timesand other publications a few years ago, Suntek still has not succeeded in selling licenses for the technology.

Gel Sciences/GelMed has had its disappointments too, but it is determined that SmartGel will not be its only success story. A similar product, trade named Smart Hydrogel, is currently being developed for drug delivery and skin care applications. Not only does Smart Hydrogel respond to temperature, it adheres to biological tissue and is sensitive to shear forces. That makes it a promising matrix material for longer lasting eye drops, nasal sprays, and sunscreens, says Ron.

Conventional eye drops are quickly diluted and washed away by tears. Although Smart Hydrogel is dropped onto the eye as a liquid, it responds to the higher temperature of the eye by becoming more viscous. Furthermore, because of its sensitivity to shear, the gel momentarily becomes liquid every time the eye blinks, allowing the gel to be spread evenly over the entire eye. The gel can thus slowly release medication to the eye over the course of hours, not minutes. Similar benefits accrue when the gel is used for nasal sprays. Nasal delivery of drugs such as insulin could replace injection, which is more difficult for patients to do themselves. According to Ron, Gel Sciences/GelMed is interested in using Smart Hydrogel to deliver, for instance, antiglaucoma and anti-inflammatory drugs to the eye and decongestants and hormones to the nose.

Sunscreens and other skin care products also could benefit from the unique properties of Smart Hydrogel. One problem with ordinary sunscreen lotions is that they are oily and the active ingredient penetrates the skin and enters the bloodstream, where it is no longer effective, Ron explains. Smart Hydrogel is water based and encases the sun-blocking agent in micelles, keeping it on the skin longer.

"Within the next two years, you will start to see products on the market containing Smart Hydrogel" for use for both humans and animals, Ron predicts.

Smart Hydrogel consists of an entangled network of two randomly grafted polymers. One is poly(acrylic acid) (PAA), which is bioadhesive and pH-responsive. The other is a triblock copolymer containing poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO) segments in the sequence PEO-PPO-PEO; this family of polymers goes by the trade name Pluronic polyols. Pluronic is a well-known pharmaceutical carrier whose hydrophobic PPO segments aggregate, leading to the distinctive gelation seen at body temperature. The PPO aggregation forms micelles, which serve to solubilize lipophilic drugs in aqueous media and allow their slow release, according to GelMed researchers. Both PAA and Pluronic have a history of regulatory approval, which gives Smart Hydrogel an edge over gel systems containing untested polymers.

Graft copolymer of Pluronic and poly(acrylic acid).

In terms of structure and properties, Smart Hydrogel bears some similarity to a family of responsive hydrogels developed by bioengineering professor Allan S. Hoffman's group at the University of Washington, Seattle. In Hoffman's polymers, which have been licensed for some uses to Gel Sciences/GelMed, Pluronic side chains are grafted in a well-defined manner onto a bioadhesive backbone--either PAA or chitosan. The latter is a hydrolysed derivative of chitin, a polymer of N-acetylglucosamine that is obtained from shrimp and crab shells.

These graft copolymers form gels when they are warmed to 37°C. By contrast, "If you physically mix [Pluronic and a backbone polymer], you don't get that gelation," Hoffman points out. The graft copolymer's gelation is critical to its performance, as his group found in in vitro drug-release experiments. For example, in a recent study submitted for publication, Hoffman and coworkers found that gelation of the graft copolymer not only prolongs the rate at which an antiglaucoma drug diffuses out of the polymer matrix, but it also slows down the dissolution rate of the matrix, another factor in the rate of drug release.

Hoffman's group also has been studying the release of anti-inflammatory proteins from Pluronic-chitosan hydrogels. The receptor proteins, intended for nasal administration, are designed to block the action of cytokines such as interleukin-1 and tumor necrosis factor, which can cause asthma and other diseases. Because the receptor proteins are anionic, they bind very strongly to the cationic chitosan backbone of the gel matrix. Nevertheless, when the proteins were released from the gel in vitro (through ion exchange and diffusion), they were found to be "totally active," Hoffman tells C&EN. This is encouraging because proteins can be denatured during storage in and release from polymer vehicles.

Chitosan may hold special promise because, unlike PAA, it is thought to be biodegradable and has been shown to enhance penetration of drugs through the nasal mucosa, Hoffman notes. Although the results to date are "very exciting," he adds, it's a long road to a useful nasal delivery system for such proteins.

Four fundamental forces control behavior of most responsive gels. These forces are responsible for the gel's ability to interconvert between two phases. In one phase, environmental conditions cause the attractive forces to be stronger and the gel collapses, expelling solvent. In the other phase, environmental conditions cause the repulsive forces to be stronger, thus expanding the gel with absorption of solvent. Source: Toyoichi Tanaka, Gel Sciences/GelMed.

A number of groups, including Hoffman's, have been exploring the potential of hydrogels for controlled delivery of insulin in diabetic patients. At the University of Utah, Salt Lake City, professors You Han Bae and Sung Wan Kim of the department of pharmaceutics and pharmaceutical chemistry and their coworkers have been developing what they call a biohybrid artificial pancreas. Basically, this is a pouch with a semipermeable membrane that would be permanently implanted in the body. A polymer solution containing clumps of insulin-releasing pancreatic cells called islets of Langerhans would be injected into the pouch. As the solution temperature reached 37°C, the heat-responsive polymer would gel, immobilizing the islets in a stable matrix. In response to rising levels of glucose in the blood, the islets would secrete insulin to bring the glucose levels under control.

Because implanted islets remain viable for only a year or less, they would have to be replaced regularly. Islets in the artificial pancreas would be relatively easy to replace: Using an ice pack placed against the skin, for example, the gel-filled pouch would be cooled below 30°C, causing the gel to become liquid again. The spent cell suspension could then be withdrawn and replaced with a fresh islet/polymer suspension. Substances that are known to stimulate islets to secrete could be incorporated in the matrix, probably reducing the volume of implant needed, according to the Utah researchers.

Recent in vitro experiments by Bae, Kim, and coworkers Brent L. Vernon and Anna Gutowska have shown that this concept is feasible. For the temperature-responsive matrix, they used a copolymer of poly(N-isopropylacrylamide) (PNIPA) and poly(acrylic acid). PNIPA is one of the most extensively studied temperature-responsive hydrogels. For this particular application, though, the Utah workers found that the copolymer with PAA has better properties than PNIPA alone, efficiently immobilizing islets isolated from rat pancreas. In response to a high glucose concentration, the entrapped islets secreted insulin for 45 days at a level comparable to free islet controls. The free islets "often disintegrated or aggregated," while the cells in the gel matrix remained intact and viable much longer, the researchers say. Small-animal tests may begin within a year, says Vernon, who presented the group's latest findings at the recent American Chemical Society national meeting in San Francisco.

At Purdue University, West Lafayette, Ind., chemical engineering professor Nicholas A. Peppas and coworkers are pursuing a rather different approach to controlled insulin delivery. They envision a device in which a glucose-sensitive hydrogel controls the release of insulin from a reservoir. Christie M. Dorski Hassan, a doctoral student in Purdue's school of chemical engineering, developed a graft copolymer of poly(methacrylic acid) (PMAA) and poly(ethylene glycol) (PEG) that is a pH-sensitive hydrogel. To make the polymer respond to glucose, she incorporated glucose oxidase. This enzyme converts glucose into gluconic acid, which lowers the pH of the local environment.

According to the Purdue researchers, at low pH values, the carboxylic acid groups of PMAA tend to be protonated, and hydrogen bonds form between them and the ether oxygens on the PEG chains. These interpolymer complexes lead to increased hydrophobicity, which causes the gel to collapse. At high pH values, carboxylic groups become ionized, the complexes are disrupted, and the gel expands because of increased electrostatic repulsion between the anionic chains.

If this gel were deposited in the pores of a porous membrane separating the blood supply from an insulin reservoir, the shrinking and swelling of the gel could control the release of insulin, Hassan and Peppas believe. Rising levels of blood glucose in the vicinity of the gel-filled pores would lead to acid production, which would shrink the gels, opening the "molecular gate" and releasing insulin.

Although Peppas believes this approach shows promise, he cautions that a practical device based on the technology is many years away. Several issues still need to be addressed, he says, "including just how such a molecular gate would be brought into contact with a patient's blood." Hassan adds that they would need to learn how to accurately control the amount of insulin delivered by the molecular gate. In her in vitro experiments, she has measured the rate of release of insulin that was incorporated into glucose-sensitive disks of PMAA-PEG graft copolymer hydrogels. Her finding: Half of the insulin is released in an initial burst in the first five minutes, and the rest is secreted gradually over three and one-half hours.

Robert S. Langer, a professor of chemical and biomedical engineering at MIT who also has studied polymer-based systems for insulin delivery, notes that researchers in this area are doing "enormously exciting science but it hasn't yet moved to the point of clinical use"--or even clinical trials. Developing suitable materials is only part of the challenge, he tells C&EN. One also has to worry about such issues as the stability of insulin in the smart polymer.

The pancreas is not the only biological drug-delivery system that researchers are trying to imitate using responsive hydrogels. A research team at Duke University and Access Pharmaceuticals, Dallas, is developing microscopic hydrogel beads that would dump drugs directly into tumors by mimicking the way bioactive substances are secreted within cells.

"We've made essentially an artificial secretory granule," says David Needham, an associate professor of mechanical engineering and materials science at Duke. In secretory cells, cellular mediators such as neurotransmitters and hormones are stored within "granules" that bud from a structure known as the Golgi apparatus. These granules are composed of a polyanionic polysaccharide matrix surrounded by a lipid membrane. In response to a chemical signal, the granule's lipid membrane fuses with the cell membrane, forming a small pore through which sodium ions and water can enter the granule. This causes the polymer matrix to swell rapidly and release its chemical contents through the pore to the exterior of the cell.

Duke's Needham with microscope image of a micropipette holding a 3-µm-wide gel bead loaded with the anticancer drug doxorubicin.

A synthetic analog of this organelle was created by Patrick F. Kiser, a polymer chemist at Access Pharmaceuticals who is studying for his Ph.D. under Needham. The analog is a spherical particle about 5µm in diameter, consisting of a copolymer made from methacrylic acid and N,N'-methylenebisacrylamide (a cross-linking agent). This hydrogel can be made to absorb as much as 200% of its own weight in doxorubicin, a potent anticancer drug. Once loaded with the drug, the gel particle is coated with a lipid bilayer. This membrane coating is essential because without it, the hydrogel bead would absorb sodium ions and water as soon as it entered the bloodstream. The gel would then swell, releasing its deadly payload short of its mark, Kiser explains.

Kiser (front) and Allen Thomas of Access Pharmaceuticals examine red fluorescent doxorubicin-loaded gel microparticles under the microscope.

Thanks to the lipid bilayer, the hydrogel beads would stay intact long enough to be filtered out of the blood by the tumor. At that point, disruption of the lipid coating could be triggered by one of several means. The chemistry of the bilayer could be primed to react to "some aspect of the disease site" Kiser suggests. Alternatively, a burst of ultrasound beamed into the body through the skin could be used to punch holes in the lipid coating. Once the hydrogel matrix is exposed to the aqueous environment, it swells within milliseconds, destroying the lipid coating and expelling the doxorubicin over the course of a few minutes. A quick release is necessary, Kiser explains, to provide a therapeutic concentration of drug to the tumor.

The 5-µm beads that have been studied so far as a prototype system are too large to use for antitumor therapy, Kiser tells C&EN. He already has synthesized the 100-nm hydrogel particles that are needed for practical application. Currently, he is working on new technology to coat the nanoparticles with lipid--a trickier undertaking than coating microparticles. Nevertheless, Kiser expects the first animal tests of this system to begin by the end of the year.

Yet another goal of Kiser and his colleagues at Access Pharmaceuticals is to engineer a series of synthetic hydrogels that are biocompatible and biodegradable. "We have a novel approach to generate a new class of hydrogel materials that will degrade into soluble polymers that can be excreted through the kidney," Kiser says.

Drug delivery is not the only hydrogel application that stands to benefit from the biomimetic approach. MIT's Tanaka believes that synthetic polymers, if properly designed, can do what proteins do: recognize a specific molecule, capture it, then release it when appropriate. For example, hemoglobin reversibly binds to molecular oxygen and ferries it from the lungs to oxygen-starved cells.

As a demonstration of this general principle of molecular recognition, Tanaka and coworkers have developed a gel that can selectively recognize, absorb, and release heavy-metal ions such as lead ions, which are toxic [Faraday Discuss.,101, 201 (1995)]. The gel consists of a copolymer of poly(acrylic acid) and poly(N-isopropylacrylamide) that is swollen below 37°C and collapses abruptly when heated to 50°C. The hydrogel contains chelating groups (carboxyl groups from two acrylic acid monomers) than can form a complex with one divalent metal ion. These groups are far apart when the gel is swollen, Tanaka explains, but when the gel is heated to the point of collapse, they come together to form an active site for capturing a metal ion. Causing the gel to swell again releases the trapped metal ions. Furthermore, the phase transition temperature of the gel is different for different metal ions because the ions serve as a "glue" to help the gel collapse. Tanaka says several companies in Japan are interested in this material for water purification.

The expansion and contraction of gels allow chemical or electrical energy to be converted into mechanical work. Because of this phenomenon, gels have long been viewed by scientists as a potential material for artificial muscle, for use in robotic actuators or prosthetic limbs. In 1991, David L. Brock, a researcher in MIT's Artificial Intelligence Laboratory, wrote in an internal document that recent research in polymer gels" offers the hope for an artificial muscle and a potential revolution in robot actuator design." But he also noted that many fundamental physical and engineering hurdles remain to be surmounted in this quest.

A number of groups have constructed contractile gel devices that can grip or lift objects. Researchers also have made progress in speeding up the response time of contractile gels, which were exceedingly slow in the beginning. But response time is still not fast enough, notes Gel Sciences' Ron, and gels for artificial muscle are "still far away from commercial reality."

But perhaps researchers at Rensselaer Polytechnic Institute in Troy, N.Y., have the answer. RPI chemistry professor Sonja Krause and doctoral student Katherine Bohon have created a gel that can respond to an electric impulse in 100 milliseconds. That's how long it takes human skeletal muscles to contract after they receive an electrical signal from the brain.

In preliminary "feasibility" experiments, Bohon used commercially available materials. She made a gel by infusing an elastic poly(dimethylsiloxane) with an electrorheological fluid, a suspension of cross-linked poly(ethylene oxide) particles in silicone oil containing salt and other additives. When an electric field is applied to the fluid, it becomes a stiff, elastic solid in about 1 millisecond. Bohon embedded two flexible electrodes in the gel and applied a 1-Hz ac electric field to it, watching it compress in less than 100 milliseconds and then stretch when the current reversed. Tiny flags she had glued to the electrodes made it easy to see the two pulsations per second.

Bohon has presented her results at a couple of meetings, but they haven't yet been published. Even so, word has gotten out, and as a result, Krause has been receiving a lot of e-mail lately. The results have sparked excitement among some scientists, Krause says, because the gel response time measured in her lab is a lot faster than the one-second to 20-minute response times seen in earlier work.

"We've got something that works, which is fun," Krause says, but now she and Bohon want to understand exactly how and why it works.

To get a handle on what's really going on in their system, the RPI chemists are now switching from commercial materials--whose composition isn't known exactly and isn't under their control--to homemade gels and electrorheological particles. Finding simpler and more controllable materials that work also may allow the researchers to develop aqueous systems and lower the rather high voltages they currently have to use.

Although gels that respond to an electric field were first reported by Tanaka's group in 1982, gels that expand and contract in response to induction heating by a magnetic field are a much more recent development. The first such gels apparently were made in 1995 in the laboratory of Steven B. Leeb, an associate professor of electrical engineering and computer science at MIT. The general strategy that Leeb and his coworkers have adopted involves embedding a ferromagnetic "seed" material inside the gel. Exposing the gel to a magnetic field causes the ferromagnetic material to warm up. This, in turn, raises the temperature of the surrounding gel and triggers its expansion or contraction. When the field is removed, the gel cools and returns to its original size.

The MIT researchers, including graduate students Deron K. Jackson and Ahmed H. Mitwalli, have experimented with three different ways to seed the gel. In the first method, they insert a tiny nickel needle into a preformed gel. In the second method, they coat micrometer-sized nickel flakes with poly(vinyl alcohol) and then mix them into the monomer solution before it gels. In the third method, they replace the water solvent with a ferrofluid, which typically is an aqueous suspension of ferromagnetic nanoparticles. The ferrofluid permeates the gel, and when excited by a strong magnetic field, it leads to significant heating, Leeb and coworkers find. Unfortunately, the ferrofluid contains a surfactant that limits how much the aqueous gels can swell, so the MIT group is trying to find ferrofluid/gel systems that do not have this limitation. Both aqueous and nonaqueous gel systems are being explored.

Gels seeded by the first two methods could be applied to implanted drug-delivery systems, actuators based on artificial muscle, and industrial systems that release and mix chemicals for reactions, Leeb says. For drug delivery, he envisions a watch-sized device containing a power supply and a coil for generating a magnetic field. The patient would position the device over the implanted gel, press a button, and activate the magnetic field. In response, the gel would contract, releasing a dose of the drug.

Gels swollen with ferrofluids could be used to create fluids whose viscosity changes in a magnetic field, according to the MIT researchers. For example, they write in a recent conference paper, "we have loaded ferrofluids with millimeter to micron diameter gel beads. When the beads are small, they occupy a small fraction of the solution volume, and the viscosity of the solution is essentially that of the surrounding ferrofluid. When the beads swell, they occupy a substantial part of the solution volume, and the overall solution exhibits a higher viscosity. With magnetic triggering, these fluids could be used to create remotely activated clutching mechanisms, vibration dampers, and molding systems."

While most intelligent gels are designed to respond to external stimuli, a research team in Japan has engineered a gel that responds to an internal stimulus. And since that internal stimulus oscillates between two states, the gel alternately expands and contracts, creating "dynamic rhythms as if it were alive," according to Ryo Yoshida, Toshikazu Takahashi, Tomohiko Yamaguchi, and Hisao Ichijo of the National Institute of Materials & Chemical Research in Tsukuba [Adv. Mater., 9, 175 (1997)].

Yoshida and coworkers made the self-oscillating gel by copolymerizing three monomers: the temperature-responsive N-isopropylacrylamide (NIPA), a derivative of tris(2,2'-bipyridyl)ruthenium(II)[Ru(bpy)3] that has a polymerizable vinyl group, and the cross-linking agent N,N'-methylenebisacrylamide. Ru(bpy)3 is a catalyst for the Belousov-Zhabotinsky (BZ) reaction, which is a classic oscillating reaction.

Self-oscillating gel made by copolymerizing N-isopropylacrylamide and a vinyl-substituted derivative of tris(2,2'-bipyridyl)ruthenium(II), with N,N'-methylenebisacrylamide as the cross-linker.

When a piece of the transparent gel is immersed in an aqueous solution containing specific amounts of malonic acid, sodium bromate, and nitric acid--ingredients of the BZ reaction--the fun begins. As the reagent solution penetrates into the gel, the Ru(bpy)3 in the polymer network begins to catalyze the BZ reaction, which is driven by the acidic bromate oxidation of malonic acid. In the BZ reaction, Ru(bpy)3 periodically changes between the 2+ and 3+ oxidation states.

When the ruthenium complex is oxidized from 2+ to 3+, Yoshida explains, the polymer chains become more hydrophilic owing to the increased charge. This leads to increased hydration of the polymer chains. And this, in turn, causes a shift in the phase transition temperature, the temperature that determines whether the NIPA-based polymer is swollen or shrunken. Thus, as the oxidation state of the ruthenium changes back and forth, the gel alternately swells (in the oxidized state) and shrinks (in the reduced state), even though the temperature remains constant.

When the gel is in the form of a small bead, it pulsates like a beating heart. But if the gel is cut into a "noodle" with dimensions 1×times×20 mm, the gel's length oscillates with an amplitude of several tens of micrometers--a change that is visible through a microscope. The chemical oscillation, whose period is about five minutes, generates a pattern of successive chemical waves in the gel, with color changes along its length. This pattern moves at a constant rate of 6 mm during each period of oscillation. Yoshida and coworkers compare the dynamic behavior they see in the gel noodle to the "peristaltic motion observed in worms."

Yoshida believes that self-oscillating gels could be used in microactuators and micropumps having peristaltic action, pacemakers, timers, and "oscillatory drug release synchronized with cell cycles or human biorhythms."

Several groups are already working to develop systems that autonomously deliver a drug in periodic, pulsed doses. For example, Ronald A. Siegel, an associate professor of biopharmaceutical sciences and pharmaceutical chemistry at the University of California, San Francisco, and his coworkers are attempting to construct a device of this sort based on an enzyme-driven pulsating hydrogel membrane. If successful, it might be used to deliver hormone pulses. For patients with certain hormonal deficiencies, pulsed delivery can restore endocrine function, whereas constant-rate delivery does not, Siegel notes.

Most smart gels are relatively homogeneous materials that shrink or swell uniformly, with no dramatic change in shape. But at the University of North Texas, Denton, associate professor of physics Zhibing Hu is making gels whose composition is engineered so that, in response to a specific stimulus, they spontaneously bend or curl into a predetermined shape such as a letter of the alphabet, a spiral, a square, or a fish [Science, 269, 525 (1995); J. Appl. Polym. Sci., 63, 1173 (1997)].

Hu and his coworkers--Xiaomin Zhang and Yuanye Chen in the physics department and Yong Li at Kimberly-Clark Corp. in Neenah, Wis.--perform their "magic" by preparing gels that have a heterogeneous or modulated structure. They use two polymers with different sensitivities, such as PNIPA and polyacrylamide. The gels are synthesized side-by-side in sequence in such a way that a part of one gel's network interpenetrates the other gel's network. In other words, across the thickness of the gel, its composition changes gradually from pure polyacrylamide, to a mixture of polyacrylamide and PNIPA, to pure PNIPA.

Using this method, the researchers fabricate bigel strips in which slabs of the two different polymers are intergrown together. The two polymers respond differently: PNIPA shrinks drastically when warmed above 37°C, whereas the polyacrylamide gel does not. The polyacrylamide gel, however, shrinks much more than the PNIPA gel when the acetone concentration of the aqueous medium increases beyond 34%. Thus, by choosing the appropriate temperature and solvent conditions, the bigel strip can be made to bend into a "C" with either one polymer or the other inside the arc. The shape changes are reversible.

Several of these bigel strips can be joined to make a gel "hand" that grasps objects with its bigel "fingers" and releases them in response to stimuli.

Hu and coworkers also have prepared shape memory gels, which have more complex modulated structures. In one example, the polyacrylamide gel is modified with the PNIPA gel at four equidistant locations so that the gel can bend only at these sites. At room temperature, the gel forms a straight line. But as the temperature is increased, the modulated sites begin bending, forming first a pentagon, and then, with further bending, a square. Compared to well-known shape memory alloys and polymers, such shape memory gels are advantageous because of their very large deformations and responsiveness to many different stimuli, Hu says.

Responsive gel strips made in Hu's lab are straight at room temperature but because of their modulated design, they bend themselves into alphabet letters at 39°C; the black bar represents 10 mm.

He believes such modulated gels eventually could find use in toys, switches, sensors, valves, and display devices. Thus far, the gels are "pretty fragile," Hu says, and their response time is slow--on the order of several minutes. Work is under way in his lab to improve these properties.

The search for gels with unusual properties is leading some researchers into less traditional polymer terrain. At Science University of Tokyo, for example, materials scientists Yukio Nagasaki and Kazunori Kataoka are studying poly(silamine)s consisting of alternating diamine and organosilyl units. These gels form a moderately tough elastic rubber. One such chemically cross-linked gel, when soaked in acidic water, swelled 16,200%, they report [CHEMTECH, 27(3), 23 (1997)].

"Because these polymers swell in aqueous media in response to not only changes in the ionic osmotic pressure but also changes in elasticity caused by anion binding and protonation, the gel hardens when it swells," Nagasaki and Kataoka write. "This is in striking contrast to the behavior of the stimulus-sensitive gels prepared so far." They believe poly(silamine)s are very promising candidates "for use in applications as varied as artificial muscle, drug delivery, and chromatographic separation."

Some scientists have suggested that smart gels could form the basis of a future "soft, wet" technology that might one day replace certain aspects of today's technology, which is based on metals and other hard materials. The automaker Toyota is said to have looked into the possibility that soft, responsive systems could replace hard materials.

In a May 1993 article on intelligent gels in Scientific American, professors Yoshihito Osada of Hokkaido University in Sapporo, Japan, and Simon B. Ross-Murphy of King's College London concluded that "soft machines will probably never replace hard ones, [but] 'wetware' may soon take its place next to hardware and software in the designer's lexicon.

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