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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

Dr. Robert Langer
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.

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."

http://www.nih.gov/news/NIH-Record/07_22_2003/main.htm