A decade ago, in the wake of lawsuits over use of silicones for breast implants, use of polymers for implantable medical devices remained an unexplored territory. Most key polymer producers spurned offering any products for implantable applications, alluding to the high ratio of risk of liability as compared to the relatively small revenue potential.
All this has changed significantly over the past few years, and the use of drug-bearing polymers in implantable devices has arrived with a bang. From a non existent base about 2-3 decades ago, it has become a US$28 bln industry in USA alone, with applications ranging from treatment of brain cancer to a potential game-changer for diabetes.
A single development in particular- that of drug-eluting stents, 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 US$5 bln market from Zero, 3 years ago. The stent technology encompasses biocompatible plastic coatings that can be timed biologically to release chemicals, even very large molecule proteins, over time. An implantable microchip that will release scores of different drug combinations over a period of weeks or even months is under development. Drug release can be triggered by a wireless electronic signal or through a programmed biological system. The new polymer technologies signal a shift in medical device design engineering. 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.
Robert S. Langer, professor of chemical and biomedical engineering at Massachusetts Institute of Technology in Boston, has had a hand in developing all kinds of innovative ways to engineer new tissue and deliver drugs to their precise targets in the body. Langer's work has also made possible the drug-eluting stent, which became available to patients with heart disease in 2003. Used for patients with life-threatening narrowing of the arteries, one such stent is marketed by Johnson & Johnson and coated with a drug called rapamycin that is slowly released into the blood vessel to prevent restenosis—narrowing of the vessel that the stent was used to widen.
Langer and his team 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. The drug-releasing polymers found a variety of medical device applications, but really paid off for the treatment of coronary disease.
Angioplasty was introduced as an alternative treatment to coronary bypass surgery around 1980. 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%. Johnson & Johnson was first on the market with the Cypher stent using a polymer coating developed by SurModics, USA. 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.
Boston Scientific's polymer engineers used SIBS-a copolymer of styrene and polyisobutylene, 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. Additionally, the butyl rubber component allows the material to expand threefold after insertion into a coronary artery. It reduces restenois rates to 5.5%. Over one million Taxus stent systems at an average selling price of about $2,500 have been supplied.
Considerable work has been done on use of biodegradable polyesters for drug delivery inside a human body. However, these polymers do not allow very controllable timed release and 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 the use the MediVas technologies for possible use in next-generation stents.
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.
Meanwhile, Langer's lab at MIT is exploring other polymeric approaches that will revolutionize medical design in other ways. This includes design of a three-dimensional polymer scaffolds and then grow cells on the scaffold in vitro in a bioreactor. This could, in 2-3 decades, take cells from the ear and grow the nose. It could involve developing a biodegradable polymer that would be like a string at room temperature and then grow into any shape you want at body temperature. The team has started 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.
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