Medical Miracles

Ten years ago, design engineers didn't dare consider use of polymers for implantable medical devices. In the wake of lawsuits over use of silicones for breast implants, major polymer producers disdained offering any products for implantable applications, citing the risk of liability compared to the relatively small revenue potential.

The Situation Has Changed

Use of drug-bearing polymers in implantable devices now is exploding. From a base of zero 25 years ago, it's a $28 billion industry in the U.S. alone this year, with applications ranging from treatment of brain cancer to a potential game-changer for diabetes. The sensational success of the drug-eluting stents in particular is triggering an explosion of development in new polymers that would disappear into the body through bioabsorbtion after their use as medical devices.

Drug-eluting stents mushroomed into a $5 billion market this year from zero three years ago. Two major companies are receiving attention on Wall Street, while Medtronic and others are waiting in the wings. At the heart of the stent technology are biocompatible plastic coatings that can be timed biologically to release chemicals, even very large molecule proteins, over time.

Under development is an implantable microchip that will release scores of different drug combinations over a period of weeks or even months. Drug release can be triggered by a wireless electronic signal or through a programmed biological system.

Another possibility, farther-out, is the construction of implantable systems that can create polymer scaffolds and cell engines to replace body parts.

Shift in Device Design

The new polymer technologies signal a shift in medical device design engineering.

At its heart is MIT scientist Robert Langer, who received the coveted Stark Draper Prize in 2002 and, earlier, the Lemelson-MIT Prize. In a break from the traditional design engineering approach, Langer did not work with commercially available plastics. He instead designed his own polymers based on specific requirements. With synthetics, Langer can capture benefits of natural materials and tailor desired mechanical properties and program polymer degradation based on reaction with water.

Speaking to the recent annual technical conference of the Society of Plastics Engineers, Langer asked, "How do materials find their way into medicine? Do they find their way because of people like us who do a lot of work in plastics? It turns out that they don't. Generally the driving force has been medical doctors, who had an urgent need."

Doctors at the National Institute of Health working on an artificial heart in 1967 sought a very flexible material and suggested polyether urethanes used in ladies girdles. "It's 38 years later and guess what the artificial heart is still made of?" says Langer. Similarly, Dacron polyester fiber used in sausage casings was the original material used in vascular grafts.

"I began to think that instead of taking materials off the shelf, what if we decided, as a strategy, to design from scratch exactly what we wanted from an engineering, biological, and chemical standpoint," Langer said.

One of the goals was to develop polymers that eroded gradually rather than all at the same time, thereby slowing the release of toxic drugs into the body. "Then we thought do we want enzymes or water to degrade the polymer? Our thinking was we didn't want enzymes because everyone has different enzyme levels. So we picked water. We also picked chemical bonds that would be water-labile." Langer and his team then met with toxicologists and picked monomers that would be safe in the human body. They chose a polymerized type of anhydride crossed with sebacic acid. Langer discovered that the rate of release could be changed through varying the amounts of sebacic acid used in the compound. "So you can simply dial in the monomer ratio and make these last whatever length of time you want." Architecture of the polymer also affects drug release rate. Tortuous internal channels slow drug release.

The drug-releasing polymers found a variety of medical device applications, but really payed off for the treatment of coronary disease.

Reopening Arteries

Angioplasty was introduced as an alternative treatment to coronary bypass surgery around 1980 (see timeline). The approach, however, was plagued by a condition called restenosis in which muscles in the artery respond to the mechanical treatment by thickening, thereby re-closing and restricting blood flow. More than half of treatments failed as a result. Introduction of bare-metal stents reduced the restenosis rates to around 25 percent.

"Our challenge was to bring that restenosis rate down into the single-digits. We and others decided to do that by developing a drug-release stent," comments James R. Tobin, president and CEO of Boston Scientific, Natick, MA. Some 80 companies globally make stents. Close to ten began development work on a polymer-coated stent five or six years ago.

Johnson & Johnson, through its Cordis unit based in Miami Lakes, FL, was first on the market with the Cypher stent using a polymer coating developed by SurModics, Eden Prairie, MN. Close behind was Boston Scientific, which quickly grabbed market leadership and saw its stock price rise substantially over 18 months. In each design, drug and polymer are mixed together and coated on a stent. After implantation, the drug is delivered right to the spot it is needed—the great advantage of the internal drug-releasing system. It's especially important when highly toxic drugs developed to defeat cancer are used. Such drugs taken systemically could have a very negative effect on patient health.

Each company in the race uses a different polymer and drug platform. The Boston Scientific Taxus stent is an example.

Taxus uses antiinflammatory drug paclitaxel, associated with chemotherapy, to treat restenosis. "It's easier to find a drug that works than it is to find a polymer that works," comments Tobin, "Finding the right polymer carrier is difficult because it must be stable, compatible with the drug, non-inflammatory, sterilizable, expandable, and able to withstand the rigors or handling and deployment without cracking, flaking, or delaminating."

Boston Scientific's polymer engineers spent a year studying several candidate materials before even considering what drug to use. "We had kissed every frog out there in the polymer area to try and find one that worked," Tobin responded to a question at the SPE conference. "We were struggling."

It turned out that Boston Scientific already owned a rubber-like material invented in the 1970s by Joseph Kennedy at the University of Akron, who told Design News that he had originally developed the material as a thermoplastic elastomer. The material is a copolymer of styrene and polyisobutylene, called SIBS, which features modifiable triblock morphology. The polymer can be designed to release the drug over different time spans. SIBS consists of soft blocks of thermoplastic elastomer and hard blocks of polystyrene. How the materials separate (as spherical, lamellar or cylindrical structures) can be programmed by varying relative weights of the two materials. The Taxus stent uses a slow release system of 30 days. Visible pores develop as the drug is released, similar to the experience in Langer's MIT lab. Taxus reduced restenois rates to 5.5 percent, according to Boston Scientific. Additionally, the butyl rubber component allows the material to expand threefold after insertion into a coronary artery.

"We have now delivered more than one million Taxus stent systems at an average selling price of about $2,500 a pop. The SIBS polymer was one of the—if not the—most critical elements that brought it all together," says Tobin.

Now there is a race on for new polymer systems to deal with another issue: the stent left behind in the body still contains some amount of powerful drug.

In Search of The Holy Grail

"The Holy Grail is a completely bioabsorbable polymer stent but it's not anywhere on the horizon for the next few years," comments Sonya Summerour Clemmons, director of business development at MediVas, LLC, San Diego, CA. For now, the push is on to commercialize a bioabsorbable coating that will release the entire drug treating restenosis.

There has already been considerable work on use of biodegradable polyesters for drug delivery inside a human body. However, these polymers do not allow very controllable timed release—the major outcome of Langer's early work. They degrade through bulk erosion. The polyesters studied could also cause an inflammatory reaction. MediVas has developed amino acid-based polyester amid copolymers that can be matrixed and conjugated in ways that allow specific release profiles from medical devices or from particles. Boston Scientific and Guidant (soon to become part of J&J) have licensed use the MediVas technologies for possible use in next-generation stents. The amount of polymer on a device is in the micrograms, Clemmons told Design News. A Rutgers University research team has developed a polymerization approach in which polymer carriers function as barriers and then degrade into products that influence the inflammatory process locally. New polymers may be able to address deep bone infections and various inflammatory diseases as well as restenosis. Several of the latest developments were described at the recent annual meeting of the American Chemical Society.

Meanwhile, Langer's lab at MIT is exploring other polymeric approaches that will revolutionize medical design in other ways. "Our plan is to design three-dimensional polymer scaffolds and then grow cells on the scaffold in vitro in a bioreactor," he says. "Let's say that someone comes in 20 to 30 years from now and they would like a new nose. You could then use computer-aided design and create any type of nose you want. You can take cells from the ear and grow the nose."

How do you avoid a difficult operation to insert a new body part, such as a nose? Langer again is using his design creativity to consider a new approach.

"We thought, could we develop a biodegradable polymer that would be like a string at room temperature and then grow into any shape you want at body temperature?" Dr. Langer and post-doctoral students began to study phase-segregated multi-block copolymers which include a series of cross links that melt at certain temperatures. At another, higher temperature, other links would take over and control the shape determined by CAD. In effect, they're biodegradable shape memory plastics. In the newest twist under study, the initiator would not be heat—it would be light from a fiber optic cable that could be inserted using minimally invasive surgery. The technology could also be used to create self-tying sutures—or even drug-eluting stents. Langer and one of his post-doctoral students, Andreas Lendlein, created a company in Aachen, Germany called mnemoScience GmbH to commercialize the discovery.

In the Works: Pharmacy on a Chip
One of the drug-releasing breakthroughs under development is a microchip loaded with pharmaceuticals or other chemicals.Based on work in the MIT lab of Robert Langer, a company called MicroCHIPS in Bedford, MA, is developing tiny silicon or polymeric microchips containing up to thousands of micro-reservoirs, each of which can be filled with any combination of drugs, reagents, or other chemicals. Preprogrammed microprocessors, remote controls, or biosensors can be used to open micro reservoirs to achieve intricate chemical release models."I'm a professor and one of the things that professors always think about is what's next that might have an impact," says Lnager. "I was watching a documentary about 11 years ago about how microchips are made in the computer industry and I thought to myself, 'Boy, would this be a great way to make a drug-delivery system.' Now if you spent 30 years of your life developing drug-delivery systems, it might turn out that any TV show might make you think that."Potential advantages of the microchip approach include small size and low power consumption, an absence of moving parts, and the capability to store and release multiple drugs or chemicals from a single device. The microchip shown here is activated through an electronic signal. Langer has also made polymeric chips that use biologically activated caps of varying molecular weights to release the drugs. It's conceivable that the device could be used in conjunction wtih an implantable insulin pump. Glucose sensors inside the mcirochip could send a message to an insulin pump implanted elsewhere in the body. Some reports have called the concept an "artificial pancreas.""In the future, what we hope to do is put little biosensors on these chips," says Langer. "Then, by using a microprocessor and a power source, we could make a smart system."


Contact Contributing Writer Doug Smock at [email protected].