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'They Said It Couldn't Be Done, But He Done It'
MIT's Langer Offers 'Blue Sky' View of Biomaterials' Potential

By Rich McManus

Photos By Bill Branson

On the Front Page...

As if to offset the leaden feel of a notoriously soggy spring in Bethesda, MIT's Dr. Robert Langer, a prolific inventor as well as professor of chemical and biomedical engineering, opened some blue skies June 16 as he discussed advances in drug-delivery systems and in tissue engineering — including new organs, blood vessels and such body parts as ears and noses — at NIDCR's annual Seymour J. Kreshover Lecture in Masur Auditorium.


The origins of many of today's most well-known biomaterials — the artificial heart, kidney dialysis machines, vascular grafts, breast implants — are entirely prosaic, Langer discussed, and are the fruit of inventors' harvesting of such commonplaces as womens' girdles (polyether urethane is a chief ingredient of manmade hearts), sausage casing (dialysis tubing utilizes cellulose acetate), Dacron clothing (the stuff of vascular grafts) and the lubricant silicone (employed in breast implants). What if, instead of looking around the household for inspiration, scientists took a more fundamental, say chemical, approach to biomaterials?

The "let's look beyond the household" approach has yielded some products now in wide use, he reported, and has such potential that Langer optimistically titled his talk, "Biomaterials and How They Will Change Our Lives."

Dr. Robert Langer
He focused first on drug-delivery systems. Most medications are commonly delivered either by injection or by mouth, which are sub-optimum methods, he said, because they typically result in peaks, which are associated with toxicity, and lows, which are associated with no beneficial effect. In the United States, more than 100,000 people die each year — four times the number of AIDS deaths — due to complications in drug-taking, he said. "Improvements in drug-delivery could have an enormous effect on human health."

Polymers, said Langer, offer the possibility of more finely tuned drug delivery; already, millions of people each year use some form of controlled drug-delivery. The nitroglycerin patch, for example, is a "powerful delivery system"; over 500 million such patches were used by patients in the past year. The Norplant birth control implants, introduced in the United States in 1991, offer more than 2,000 days (in excess of 5 years) of contraception, and are used in at least 50 countries. Many medications rely on the delivery of comparatively large molecules of drug through polymers, a feat that was not considered possible back in 1974, when Langer was finishing his graduate work in chemical engineering at MIT. He described a postdoctoral stint in the laboratory of Dr. Judah Folkman during which Langer attempted to deliver, via polymers, large molecules in unadulterated form.

"The conventional wisdom was that it couldn't be done," Langer said. "I found more than 200 ways to get it to not work, and then luckily found one that worked." His new approach used microspheres of polymer to release peptides and proteins and other molecules of varying size. Through experimental studies, Langer and his colleagues found that by chemically adjusting the pore structure on microspheres, they could achieve a drug-release range from one day to 3 years.

"We learned gradually how to regulate release," he said, noting that insulin can be delivered using this method. Another drug, Lupron Depot, used to treat endometriosis and prostate cancer among other conditions, offers controlled release over the course of 4 months.

Langer's lab is currently asking if computer-type chips can be used to store and deliver chemicals. He described small chips with built-in wells of drug — "pharmacy on a chip" — in which a small voltage applied to a gold membrane covering the well "uncorks" the material in the well. "We can put hundreds of these wells on a chip smaller than a dime," he said. "A chip of one cubic centimeter can hold 500 mg of drug...Our vision for the future is that someday you could open the wells as easily as you open your garage door with a remote control device using radiofrequency." Deeper into the future, he predicted, "you could put biosensors on the chips so that you'd get direct feedback control, which would be very useful in delivering a drug such as insulin. The chip could transmit an electronic record of when the patient took the drug, and how the body responded."

Langer has made a career of overcoming obstacles.

The remote control of drug delivery could also be a boon in that large subset of patients who, owing to disease, are prone to forget to take their medications, he suggested.

Langer's most dramatic vignette involved the dozen years that passed as a cast of academic reviewers successively thumbed their noses, via a series of seven brick-wall objections, at Langer's attempt to develop new polymers and also to apply controlled drug delivery to a devastating brain cancer known as glioblastoma multiforme. In a rousing indictment of timid peer review, Langer showed not only how each objection was overcome by a succession of brilliant graduate students and postdocs in his lab, but also how those grad students and postdocs — and he named them and their current institutions — are now chairs and department heads of leading medical centers or presidents of major companies.

From 1981 to 1993, the approach of lining the surgical cavity in brain tumors with a degradable polymer that wouldn't dull the effect of an anticancer drug called BCNU, gained credibility. In 1996, the Food and Drug Administration approved the therapy, Langer related, which was "the first time in more than 20 years that a new brain tumor therapy was introduced." The technique has matured to the point that drug-immersed wafers are also sewn into the surgical cavity, in both brain and spinal surgery. Stents coated with polymer-drug combinations are also being employed successfully in heart disease, Langer added.

But what about the many diseases not amenable to drug therapy, Langer asked. "Could you tissue-engineer a new organ, or new tissues?" His lab has proven the concept, in an animal model, that you can start with a specific tissue type, grow a biologically friendly scaffold — say a nose or an ear — outside the body, seed the scaffold successfully with the tissue, then reinsert the part to the host. "Someday, we'll be able to custom-make tissues in any shape you want," he predicted.

Langer shows the possibilities of tissue engineering.

He described "shape-memory" polymers that, under one set of temperature conditions, are threadlike, but which become, at body temperature, something new. "A new nose, for example, could start out as a thread that could be noninvasively inserted through a small incision." He showed videos of polymer threads that knot themselves, or coil themselves, in response to changes in temperature.

Langer envisions growing human embryonic stem cells, converting them to endothelial cells and then forming functional blood-carrying microvessels, which can mature into vessels suitable for implantation.

His final film clip depicted spinal cord repair — using an artificial scaffold seeded with neural stem cells — enabling a hobbled rat to regain considerable function in its legs. "It's not a cure," he cautioned, "but it is progress.

"Thirty years ago, advances such as these would have been viewed with a great deal of skepticism," he concluded. "We hope one day to profoundly improve human health throughout the world."

Dr. and Mrs. Seymour Kreshover take in Langer's talk from the front row.

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