Another company, ChipRx Inc., in Lexington, Ky., has also pursued bioMEMS-based drug delivery, but development of its first product, an implantable matchstick-size drug-delivery vehicle that uses electrically activated artificial muscles to open and close drug reservoirs, is on hold for now. Marc Madou, cofounder of ChipRx and an engineering professor at the University of California at Irvine, says that for the immediate future ChipRx intends to concentrate on making genetically engineered proteins that might be dispensed as part of a closed-loop device.

With or without sensors, developers still don't know how long and how reliably bioMEMS will function once implanted into living systems, a factor that will determine whether doctors and their patients accept the devices. The objective is to design implants that can meter out precise doses of drugs for months or years before they must be removed or replaced. MicroChips' Santini says that his company has unpublished data from ongoing experiments in animals demonstrating that its chip has continued to release a drug for more than three months.

As with any medical implant, fouling might limit the useful lifetime of a bioMEMS device. In fouling, cells and molecules of the body's immune response stick to the surface of an implant, preventing it from functioning properly. Many implants may also become surrounded by a thick capsule of scarlike tissue that essentially blocks them from communicating with the rest of the body. Coating the implants with anti-inflammatory drugs might prevent them from being attacked by the immune system.

"Fouling is a real biggie" among the issues confronting bioMEMS, says Burton Sage, cofounder and chief scientific officer of Therafuse Inc., in Carlsbad, Calif. His firm is developing wearable (but not implantable) pumps that exploit MEMS technology by using a tiny needle to administer precise doses of drugs, such as insulin, through the skin.

Sage adds that it is impossible to predict now whether fouling will foil the prospects of bioMEMS. The degree of fouling appears to depend on the chip's location in the body, the type of drug the device contains, and the kinetics of that particular drug's release and diffusion.

In the case of implantable sensors—a blood glucose meter, for example—bioMEMS might even be used to compensate for fouling, asserts Santini. Such sensors are now effective only for a few days or weeks, after which they become irreversibly clogged. Encasing multiple sensors in a bioMEMS device could yield an implant in which wells could be opened, one at a time, to reveal a fresh sensor when the old one has become clogged beyond use.

Therafuse's Sage wonders about another lifetime issue: how to refill the implants. "How do you put enough drug in there for the long term?" he asks. Retrieving and refilling a bioMEMS device would require outpatient surgery. To circumvent this, some scientists are designing implants with drug chambers that can be refilled from syringes without removing the devices from the body.

Among those who might be willing to undergo repeated implant placement, Sage says, are patients who have had a heart attack and are at high risk for another. In such instances, a bioMEMS could be loaded with a clot-dissolving drug or the heart stimulant epinephrine (also known as adrenaline). The patient could activate the implant at the first symptoms of a heart attack.

The ultimate goal, however, is to take the patient out of the loop by relying on microprocessors to do the regulation automatically. "The whole reason for wanting intelligent drug-delivery technologies is so you can do closed-loop sensing and drug administration," says Santini, whose company is working on precisely that challenge. Putting sensors and drug reservoirs on board the same chip could yield a device that would automatically monitor the presence of a given molecule in the blood and then administer the drug precisely when it is needed.

Such an approach would be a huge boon to people with congestive heart failure, says Nader Najafi, founder and president of Integrated Sensing Systems Inc., in Ypsilanti, Mich. In that disease, imbalances in water regulation by the body lead to fluid buildup around the heart, impeding its ability to pump blood. An automatic sensing and delivery system might detect increases in pericardial fluid and reduce the buildup by releasing a diuretic, a drug that causes the body to eliminate water. Congestive heart failure, which afflicts an estimated 15 million people worldwide, is the most frequent cause of hospitalization among those 65 and older in the United States and a major cause of death if not treated in a timely manner.

For now, Integrated Sensing Systems is conducting early research into the sensor side of things by attempting to develop a wireless, batteryless, implantable pressure sensor for use in congestive heart failure, according to Najafi. The company is still working out the details of exactly how the device would function; researchers at the company eventually intend to couple it to a mechanism for dispensing drugs to treat the disorder.

Under the company's current plans, physicians would implant a pressure-sensing bioMEMS into a patient's left heart ventricle during outpatient surgery by threading a cardiac catheter through the blood vessels and into the heart chamber. A signal from the sensor would then activate a diuretic drug-delivery system.