The measurement principle of transcutaneous glucose sensors

The transcutaneous sensor has a very thin, flexible filament, much finer than a needle, which is inserted just under the skin, into the fatty tissue. This filament does not sit in a blood vessel but in the fluid between the cells of that tissue, called interstitial fluid. The sensor does not measure directly from the blood but assesses the glucose concentration in this fluid, which closely follows the blood glucose [1].

The measurement is done electrochemically. The sensor converts the glucose concentration into a very small electric current, with the help of an enzyme and an electrode (that thin filament) [2]. The more glucose there is in the interstitial fluid, the larger the current generated locally. The result may lag slightly behind the blood glucose level when that value changes rapidly. The glucose in this fluid synchronizes with the blood values with a small delay [3].

The tip of the filament under the skin is covered with an enzyme fixed to its surface, most often glucose oxidase. This enzyme is a biological catalyst, meaning it speeds up the chemical reaction of glucose with oxygen without being consumed in the process [4]. It is the part that actually recognizes the glucose and turns the sensor into an instrument dedicated specifically to glucose, not just a plain general electrode.

The enzyme's main role is to give the sensor specificity, that is, to respond to glucose and largely ignore other substances [5]. This selectivity is not complete, though: with some models, substances such as paracetamol or vitamin C can alter the reading [5]. Without this enzyme, the sensor could not tell glucose apart from the other molecules in the interstitial fluid. Some older sensors use a related enzyme, glucose dehydrogenase, but the measurement principle remains the same [5] [6].

The enzyme (glucose oxidase) makes the glucose react with the oxygen in the interstitial fluid. This reaction produces gluconic acid and hydrogen peroxide (H₂O₂). The amount of hydrogen peroxide produced is directly proportional to the glucose concentration, that is, more glucose means more hydrogen peroxide [4].

The hydrogen peroxide reaches the sensor's electrode, where it breaks down and releases electrons, which form a very weak electric current. This current is essentially the signal picked up by the sensor, and its magnitude reflects the glucose concentration in the interstitial fluid, as the figure below shows [5].

Yes, the reaction consumes a very small amount of glucose. Each glucose molecule that reacts with the local oxygen turns into gluconic acid, so it is used up on the spot. The enzyme attached to the filament is covered by a special membrane. This membrane lets only a small, controlled amount of glucose through, so the reaction stays limited: its rate is set by the membrane, not by the amount of glucose around it [7].

This consumed amount is small enough not to lower the blood glucose or deplete the glucose around the filament, so the later readings are not affected either. The body continuously replenishes the glucose in the interstitial fluid from the glucose in the blood. The enzyme is a catalyst and is not consumed, but over time both it and the membrane can wear out, which is why the sensor has a limited lifespan [8].

What you see as a simple filament under the skin actually contains several electrodes, arranged in very thin layers and insulated from one another on the same flexible support. Each electrode has its own role:

• the working electrode is coated with enzyme and produces the signal;
• the reference electrode holds a stable voltage, used as a reference point;
• the counter (auxiliary) electrode closes the electrical circuit [6].

The electronic component attached to the sensor keeps a constant voltage between the working electrode and the reference electrode. The chemical reaction does not change this voltage, only the strength of the current. The higher the glucose concentration in the interstitial fluid, the greater the strength of the current passing through the working electrode.

Some systems add a fourth electrode, without enzyme, which measures the background noise, that is, the small signal present even when there is no glucose. The signal from this electrode is subtracted from the useful signal, in order to reduce the influence of other substances.

The measured current is read continuously by the electronic component (transmitter). A calibration factor converts this current into an estimated glucose value [2]. Many modern sensors are factory-calibrated, while others occasionally need a check and possibly a recalibration with the glucometer [9]. The system's algorithms, meaning the programs that run in the transmitter or in the phone app, smooth the small electrical variations and partly correct the delay between the interstitial fluid and the blood [3]. The result is expressed in mg/dL or mmol/L and sent wirelessly to a phone or another receiver.

Yes, the sensor needs a small source of power, usually a battery housed in the transmitter. This power maintains a constant electric potential on the electrode, and the chemical reaction catalyzed by glucose oxidase generates a current proportional to the glucose concentration [6]. It also powers the signal processing, the internal memory and the wireless sending of the data to the phone or receiver [10].

Power consumption is very low, so a tiny battery is enough for the whole time you wear the sensor. Most continuous monitoring systems work for between 7 and 15 days (recently even 21 days) [11] [12]. After this interval the sensor is replaced with a new one, together with its power source. On older models the transmitter is reused across several sensors [10].