Focus
Getting under the skin: fter years of research and— according to some researchers— low levels of research funding, progress is finally being made toward implantable continuous glucose monitors. Some of these devices have been successfully tested in animals and are making their way into limited human trials, and commercial devices seem to be moving closer to reality. Two very different types of implantable glucose sensors are being proposed—fully implantable and percutaneous (worn through the skin). The fully implanted devices, which include electronics and a battery, may be several cubic centimeters in volume. These devices are designed for longevity (months to years) and are intended to be implanted by a physician either subcutaneously or in a blood vessel. The percutaneous sensors are needlelike or inserted through a needle and are designed to operate for a few days and be replaced by the patient.
Implantable electrochemical glucose sensorsaremoving closer to commercialization. night and can cause the patient to lose consciousness. For practical reasons, nighttime variations are often neglected, but nocturnal hypoglycemia is a particular worry for the parents of young diabetics. The best way to avoid such dire consequences is to frequently monitor the blood glucose levels. However, even the most diligent patients who perform fingersticking many times a day achieve only a poor approximation of continuous monitoring. Most researchers in the field agree that an appropriate first goal for a continuous glucose monitor is a hypoglycemia alarm that alerts patients when their glucose levels drops below a threshold value.
Why continuous monitoring?
Diabetics must frequently check their blood glucose levels by "fingersticking" and adjusting their insulin dosage, food intake, and physical activity to keep the glucose levels as close to "normal" as possible. Too much glucose (hyperglycemia) indicates that more insulin is required, and too liitle glucose (hypoglycemia) requires immediate action to raise the levels. Hyperglycemia causes most of the long-term consequences of diabetes, including blindness, nerve degeneration, and kidney failure. However, in the short term, the immediate danger isfromhypoglycemia (sometimes called insulin shock) which can occur at any time of the day or 594 A
Electrochemical aspects
Most implantable glucose sensors are amperometric enzymatic biosensors. Three general strategies are used for the electrochemical sensing of glucose, all of which use immobilized glucose oxidase, an enzyme that catalyzes the oxidation of glucose to gluconic acid with the production of hydrogen peroxide. The first detection scheme measures oxygen consumption; the second measures the hydrogen peroxide produced by the enzyme reaction; and a third uses a diffusable or immobilized mediator to transfer the electronsfromthe glucose oxidase to the electrode. Although
Analytical Chemistry News & Features, September 1, 1998
noninvasive glucose monitors using near-IR spectroscopy have also been suggested, they are not discussed here. David Gough and his colleagues at the Department of Bioengineering at the University of California-San Diego, have developed a sensor of the first type. A cylindrical sensor was designed to allow glucose and oxygen to diffuse into the enzyme region of the sensorfromone direction, but only oxygen diffuses from the other direction (1). This design helps eliminate what Gough calls the "oxygen deficit", the low ratio of oxygen to glucose that exists in the body. The modulation of oxygen transport to an oxygen electrode by oxygen participation in the reaction provides the means for glucose determination The enzyme catalase is immobilized with the glucose oxidase to remove the hydrogen perfwiHp which can Qnnrten the active lifetime
of glucose oxidase (Catalase disnroportionation of hydrogen peroxide to oxwen and water") This sensing method requires an additional oxygen electrode setup to indicate the background concentration of oxygen. Hydrogen peroxide sensors measure the product of the enzymatic reaction on an anodically polarized electrode. One of the advantages of hydrogen peroxide sensors is that the signal increases with increasing glucose concentrations. However, the oxidation
Implantable glucose sensors gen remains in the system, the mediator must compete effectively with the oxygen for the electrons. In the past, ferrocene has been used as a mediator but it is diffusable and toxic. A more recent version of the mediator sensors is the "wired" glucose oxidase electrode designed by Adam Heller and his group in the Department of Chemical Engineering at the University of Texas at Austin. The mediator does not leach because it is bound to a polymer, which is cross-linked. The glucose oxidase is tethered to the electrode with a hydrogel formed of a redox polymer with electrochemically active and chemically bound complexed osmium redox centers (4). Here's a sensor—What next?
of hydrogen peroxide requires an applied potential at which many other species commonly found in the body are electrooxidizable, creating the possibility of interference. The most problematic species are urea, ascorbate (vitamin C), urate, and acetaminophen. Interferences are minimized with semipermeable membranes that restrict their passage. The enzyme reaction still requires oxygen, which is usually assumed to be adequate. Various researchers have championed the approach of hydrogen per-
oxide detection, including George Wilson of the University of Kansas (and his French collaborators, Gerard Reach at the HotelDieu Hospital in Paris and Jean-Claude Klein at the Laboratory of Mathematical Morphology) (2) and Stuart Updike of the University of Wisconsin-Madison (3). Sensors that use nonleachable electrochemical mediators circumvent the oxygen deficit by using a species other than oxygen to transfer the electrons from the glucose oxidase to the electrode. Because oxy-
Before a glucose sensor can provide continuous measurements, it must be placed in the body. There are two broad visions of how this would be done. In the first case, the sensor would be worn through the skin (percutaneously) as a needle and would have a tiny wire outside the body connected to a readout device such as a watch or a belt pack. In the second type, the entire device, including a transmitter and a battery, would be totally implanted in the body and would communicate with an external receiver via radio telemetry.
Analytical Chemistry News & Features, September 1, 1998 5 9 5 A
Focus Percutaneous or fully implantable— which would be better? Both have potential advantages and disadvantages. In either case, the body responds to the implant as an insult and produces a specialized biochemical and cellular response to protect the body from the invader, says Updike. This foreign body response can lead to the development of a foreign body capsule around the implant. In the worst case, the defense mechanism may reduce the flux of glucose and oxygen to the sensor. The percutaneous aooroach aims to acquire data during the first few davs of this tissue response For most fullv implantable stens must be taken to deal with the longi p r n l a s n w t s of tVii«; rpQnnn
