Metering from the inside

Implantable glucose sensors are inserted beneath the skin or inside a blood vessel. This technology has been in development for quite some time, but the first product, MiniMed's monitor, became commercially available only in the past few years [see "photo"]. Such monitors, which rely on advances in chemical sensors and biocompatible materials, are a step toward the ultimate goal: a glucose sensor that can be connected directly with an insulin delivery system to make an artificial pancreas, the organ that controls blood glucose levels in the body.

MiniMed's device operates for up to three days—not a permanent solution, but one that yields enough information to improve a person's treatment regimen. The device records glucose levels for a healthcare professional to view on the patient's next office visit. First the user performs two to four finger-prick blood glucose measurements to calibrate the device, which then supplies readings at five-minute intervals. Clinical researchers report identifying low glucose levels at night and high glucose after a meal that were previously unobserved by periodic pinpricks.

MiniMed's product is an example of an enzymatic electrochemical sensor. In brief, an enzyme called glucose oxidase is fixed to an electrode and catalyzes the conversion of glucose into gluconic acid and hydrogen peroxide. The hydrogen peroxide then reacts at the sensing electrode, which is typically biased at 0.6 V, resulting in a measurable electric current [see "equation"].

Generally, implantable sensors can be categorized by the site of implantation and the method of measuring glucose. Subcutaneous sensors are inserted beneath the skin through a needle and measure glucose in interstitial fluid, the liquid between the cells. Other sensors are surgically affixed to the inside of a large vein and measure glucose in blood. Most sensors, like the MiniMed device, employ an enzymatic conversion step to turn glucose into a chemical signal that can be easily measured electrochemically or optically.

The main challenge in developing a glucose sensor for implantation beneath the skin or in a vein is to maintain the sensor's performance when it is exposed to the inside of the body over long periods of time. Almost without exception, interactions with the body cause a decrease in sensor performance [see illustration, "AutoSensor"]. For example, the body's immune system inevitably launches an attack and tries to encapsulate the sensor in protein. The glucose-blocking barrier thus created blunts sensor sensitivity and lengthens response time.

On another front, the body's warm, salty environment corrodes metal electrodes and can inactivate enzymes, which leads to loss of measurement sensitivity and stability. Movement by a person wearing the device can create artifacts and noise that decrease sensitivity and specificity to glucose signals and also produce mechanical stresses that affect stability.

Many other interactions with the body's environment must also be dealt with. For instance, substances such as vitamin C and acetaminophen may react at the electrode, creating spurious signal. Such chemicals can also destroy the hydrogen peroxide before it can react at the electrode, stealing signal from the system. To minimize this effect, many implantable systems include membranes that keep these substances from the sensor.

Another problem is that when glucose levels are high, oxygen may become the limiting reactant in the electrochemical sensing scheme that MiniMed and others use. The result is signal saturation and a limited system operating range. To combat this drawback, some investigators have introduced membranes that limit the amount of glucose that reaches the sensor. Or they do away with the need for oxygen by using sensing schemes that rely on alternative reactions.

Still another defense against the body's attacks is microdialysis. In this technique, dialysis tubing, made from a material that allows only small molecules to pass across it, is implanted under the skin. The tubing has a special fluid pumped through it, into which glucose diffuses. The fluid is then collected and measured with an external sensor. This strategy prevents proteins from encasing the sensor.

The design of MiniMed's sensor addresses some destructive interactions with the body. It is built on a flexible substrate to minimize the effects of motion and to fit more comfortably in the patient. The sensor is also coated with a biocompatible polyurethane to minimize the immune system's response.

Besides the subcutaneous types, some fully implantable glucose measurement systems are being developed. These systems have the ambitious goal of providing continuous blood glucose measurements for years on end and interfacing with an implantable insulin pump. The result is closed-loop control of glucose levels—in effect, an artificial pancreas.

Medical Research Group, known as MRG (Sylmar, Calif.), is developing such a device to measure glucose in the right atrial junction—the wide entrance to the right atrium of the heart. It is at this junction, where blood flows fast through a large diameter vessel, that the device is least likely to cause blood clots or blood flow perturbations. By obtaining a signal directly from blood instead of from subcutaneous tissue, the sensor's response time is minimized, making it more suitable than the subcutaneous type would be for a closed-loop system.

The sensor has been tested in dogs and in humans for months at a time, and the closed-loop system has controlled glucose levels in dogs for a full week.