by Trevor Thieme

December 01, 2001
from DiscoverMagazine Website

Above, left: In Langer's chip, medicine is stored beneath 50-micrometer squares of gold membrane (top).

A small electric charge administered either remotely or via a small battery dissolves the gold cap, releasing the drug (bottom).

Above, right: One prototype chip holds 100 drug-containing reservoirs (top).

The circuitry on the reverse side (bottom) directs electric current to each reservoir.

Photographs:

left (2) Courtesy of Microchips, Inc./Nature 397, 335-338 (1999). Macmillan Magazines Ltd.;

right (2) Courtesy of Microchips, Inc./Carita Stubbe
 

When Robert Langer looks out the window of his lab on the edge of the Massachusetts Institute of Technology campus, he sees the future of medicine writ large. To the right sits the Media Lab, a hotbed of silicon-based innovations such as interactive cinema and wearable computers. To the left is MIT Medical, the hub of campus health care.

And here at the crossroads, Langer and his collaborators are working on a device that fuses the best ideas from both institutions.

"We are applying what's been used in computers to chemistry," he says. "We're creating a pharmacy on a chip."

Langer's team is one of several research groups nationwide developing programmable implants that could revolutionize the way drugs are administered and overcome one of the most common obstacles to effective medical treatment. All too often, getting the right dose of a pharmaceutical to the precise target proves difficult to achieve.

Pills are problematic because the digestive system breaks down many therapeutic compounds before they can reach the bloodstream. Injections bypass the stomach but are expensive and inconvenient, as well as difficult to self-administer. Worst of all, both needles and pills can cause dangerous fluctuations of drug concentrations. For example, too much insulin kills a diabetic; too little can put him in a coma.

Langer's proposed solution is a dime-sized microchip pockmarked with up to a thousand drug-filled reservoirs, each sealed with a gold cap and wired to a power source.

Electrical signals pop open the caps, dispersing their contents. Placed beneath the skin near the site of an injury—a sore knee, for instance—one of these smart pills could deliver anti-inflammatory or antiarthritic medication right where it is needed.

Or, implanted directly in a tumor, a microchip could deliver high doses of toxins to the malignant cells without damaging the surrounding organs.

"That is the beauty of this device—you can set it up any way you want," Langer says.

And in the long run, he predicts that the pharmacy chip could even spell the end of today's one-size-fits-all drug treatments. Langer plans to link the programmable chip with sensors and microprocessors that adjust the timing, dosages, and even mixes of medications to a patient's individual needs rather than to societal averages.

The sensors could also function as 24-hour health monitors. Physicians might download a patient's blood biochemistry readings on demand via a wireless link, evaluate the response to medication, and adjust the treatment by remote control. Frequent medical attention could become much cheaper and simpler to schedule.

Preliminary tests look encouraging. Last year, Langer's team successfully used an implant to deliver medication into a rabbit's eye without irritating the surrounding tissue. A related experiment on rats demonstrated that the device can release a precisely controlled drug dose.

The technology will require a host of design refinements before tests on humans can begin, however. In its current form, the pharmacy chip is hardwired to an external battery pack and an unwieldy set of control wires.

"The packaging has to become highly integrated and reliable, able to store its own programming. Our ultimate goal is to have no user intervention at all," says John Santini, president of MicroCHIPS, a company based in Cambridge, Massachusetts, created to commercialize the device.

He anticipates clinical trials in two to three years; a finished product could hit the market in 10 years.

Meanwhile, Marc Madou and colleagues at his Ohio-based company, ChipRx, are developing an alternative implant: a smart pill with muscle power. Madou's invention is a thin, torpedo-shaped device, about the size of a matchstick, with one or more drug chambers at its center. Like the Langer chip, this device would be surgically inserted just below the skin, but the way the device dispenses drugs is quite different.

The outside of the torpedo is peppered with thousands of microscopic rings composed of an elastic mixture of hydrogel and polymer. Each ring behaves like a biological muscle, contracting when stimulated by an electric current and expanding when the voltage is reversed.

These artificial sphincters do the work of Langer's gold caps in controlling the release of medication, but the rings are far more controllable.

In ChipRx's smart-pill prototype, microscopic rings open and close like sphincters to release medication.

The implant itself is the size of a matchstick.
Photographs courtesy of Marc Madou/Nanogen

"We are mimicking Mother Nature's cellular design to open and close channels between the drug capsule and the outside world," says Madou.

His design takes the biological connection a step further by activating the rings of hydrogel with biosensors, engineered proteins that bind to target molecules. For example, an implant for a diabetic would have a biosensor that reacts to glucose. When a large enough number of glucose molecules latch onto the biosensor, it would change shape, triggering an electric current that would shrink the muscles and expose the drug chambers full of insulin. As glucose levels drop to normal, the system would shut off.

ChipRx has just finished assembling a working version of this intelligent implant.

The device is currently undergoing a basic feasibility test in which it will release its contents into a beaker on command. Although the results are not in yet, pharmaceutical giants such as Bayer and Pharmacia & Upjohn as well as Procter & Gamble have expressed an interest.

And Alison Cole, a program director at the National Institute of General Medical Sciences in Bethesda, Maryland is fairly optimistic.

"These technologies add a level of elegance and sophistication that we haven't seen before," she says, "but they'll have to overcome the same challenges that any drug-delivery system must face."

To begin with, any implant has to contend with the body's natural defenses against foreign intrusions.

"We are designing our device to resemble the surface of cells and tissues, so that the immune system will pass it by without responding," says Patricia Eisenhardt, vice president of ChipRx.

Although the company hasn't tested its camouflage yet, a similar approach has worked well on artificial heart valves and other devices.

In addition to the biological challenges, both Langer and Madou face technological and legal hurdles, which may be even more daunting.

"Every time you add a level of complexity, you add a method of failure," says Santini.

Langer's method is to strive for simplicity, eliminating moving parts in order to minimize the risk of breakdown. Madou is taking an opposite approach, working on backup systems that include a pump to unclog a blocked chamber and a safety valve in case an artificial muscle gets stuck. The ultimate nightmare confronting both inventors is a smart implant that misfires and dispenses a fatal overdose.

One such failure could discredit the technology and bankrupt its developers.

Over the next decade, smart implants will also face challenges from other alternative drug-delivery systems. A number of teams are working on inhalable drugs to treat diabetes and other diseases. The first light-activated medication has been approved in Europe to treat skin cancer. And some nanotechnology optimists remain bullish on the Fantastic Voyage scenario—microscopic robots that traverse the bloodstream performing medical repairs.

Kazushi Ishiyama at Tohuku University in Japan has developed pinhead-sized, magnetically controlled spinning screws. He envisions smaller versions swimming through veins, dispensing drugs or burning away cancerous tissue.

Given all the technical innovations in the field, Langer is confident that today's awkward treatments—multiple pills that must be taken at precise intervals interspersed with frequent, time-consuming checkups—are on the way out.

It's simply a matter of giving a new twist to the PC revolution, so that patients can benefit from the shotgun marriage going on in Langer's lab.

"Here microchips mean something different than they do to the rest of the world," he says. "Here they mean drug delivery."