What are the generations in glucose biosensors?

When we think about generations in technology, perhaps the first thing that comes to mind is the telecommunications network. First was 1G and now we are already at 5G.

With each new generation we have improved the speed, complexity and variety of devices with which we communicate every day.

Like the telecommunications network, biosensors also have several generations. With each one of them, biosensors become faster, more reliable and gain more functionalities.

From all biosensors, the glucose biosensor is the one that has been on the market the longest. Therefore, it is the biosensor that has experienced the most generations. Below we explain more about them.

How many glucose biosensors exist to date?

To date we count 3.5 glucose generations. We understant that this is a weird number. How is it possible to have half generations? It all depends on how generations are named. We will explain more about this “half” generation below and why it was not considered its own generation.

1st generation glucose biosensor

The first glucose biosensor generation uses an enzyme, normally glucose oxidase, to convert glucose into glucolactone and release electrons.

This enzyme, requires oxigen to be regenerated and continue catalyzing the reaction. During this regeneration, the oxygen dissolved in solution depletes and hydrogen peroxide is produce.

In this generation, the produced hydrogen peroxide is what is actually utilized to detect glucose. By the electroreduction of hydrogen peroxide we can determine the amount of glucose in the sample by measuring the generated electrical current.

The main inconvenience of this first generation of glucose biosensors is that the signal depends on the concentration of oxigen dissolved in the sample. As a result, this can lead to quantification errors if oxigen becomes the limiting factor of the reaction.

2nd generation glucose biosensors

The 2nd generation of glucose biosensors seeked a solution of the problem encountered by the 1st generation: the dependence on oxigen.

To eliminate this dependence, an alternative to oxigen was researched.

In the 1st generation glucose biosensor, oxigen acts as the natural mediator of the reaction. It regenerates the catalytic centre of the enzyme so that it can break down another glucose molecule.

This regeneration occurs via an electron transfer between oxygen and the catalytic centre of the enzyme. However, this electron transfer is not excllusive of oxigen. There are other molecules, like ferrocene, that are able to exchange electrons with the catalytic centre of the enzyme.

By substituting oxigen with another molecule, like ferrocene, glucose biosensors improved their reproducibility. They no longer depended on the dissolved oxigen in the patients blood.

However, these biosensors are not suitable to be used in implantable devices. Most molecules used to subsitute oxigen in the sensor in this generation are free in solution. Therefore, should these devices be implanted into a patient, the concentration of this free mediator would vary with time. As a result, the sensitivity of the biosensor would rapidly decay. Moreover, should the mediator chose be toxic, being free in solution would lead to health issues.

2.5th generation glucose biosensor

We now reach the “half” generation. This generation, is very similar to the 2nd generation. In fact, so similar that it did not qualify for a full generation.

The working mechanism is the same as the 2nd generation glucose biosensor: substitute oxigen with an artificial redox mediator. For this reason it was not considered to be worthy of a new generation.

However, there is one difference. In the 2.5th generation, the mediator is not free in solution. Instead, it is bonded to the electrode.

While this small difference may seem trivial, it is of vital importance to develop wearable glucose biosensors.

Thanks to the bonded mediator, its concentration remains constant. This helps maintain the sensitivity of the biosensor for longer. Also, this format minimizes the potential toxicity concerns. For this reason, 2.5th generation glucose biosensors are on of the best options to develop implantable glucose biosensors.

3rd generation glucose biosensors

While generation 2.5 has proven useful for a plethora of applications, biosensor research continued with new ideas to further improve them.

This is the case for the 3rd generation of glucose biosensors.

In this generation the goal is to eliminate the mediator completely and use the electrode to exchange electrons with the catalytic centre of the enzyme. This technology is known as Direct Electrode Transfer (DET).

However, this technology is still in development and only a handful of companies claim to be able to perform DET and commercial devices are not available.

The main challenge of the 3rd generation is the structure of the enzyme itself. Since the catalytic centre is buried deep in the enzyme, it is too far to be able to transfer electrons directly from the electrode.

For this reason, 3rd generation glucose biosensor development focuses on 2 lines of research:

  • New electrode materials capable of exchanging electrons at longer distances
  • New artificial enzymes with a protein structure displaying a more exposed catalytic centre

To date, there have been numerous interesting results in academic literature and we hope to see commercial 3rd generation glucose biosensors soon.

What about the 4th generation of glucose biosensors?

Up until now we have discussed the existing glucose biosensor generations and how they have improved glucose detection over the years. But what’s beyond the 3rd generation?

While 4th generation glucose biosensors have been envisioned in multiple ways, it has not been determined what will be the basis of this technology yet. Still there are a number of issues to fix with glucose biosensors, so technologies capable of sorting these challenges could become the 4th generation of glucose biosensors.

Issue 1: calibration

While implantable glucose biosensors greatly improve the quality of life of diabetic patients by reducing the amount of times they need to prick their fingers to take blood sugar readings, they do not remove the need for this measurements completely.

Often, implantable biosensors require an initial calibration and/or periodic to get precise measurements.

This means that the patient has to combine the implantable device with glucose strips. Which is a great hurdle towards market adoption.

A possible 4th generation would be a self-calibrated glucose biosensor like the one Madelecs is working on.

Issue 2: long term stability

The second great challenge of glucose biosensors is their long-term stability.

This challenge, in fact, is not exclusive to glucose biosensors. It is common in all biosensors.

Biological receptors have a tendency to degrade over time, which leads to short shelf lifes and special storage requirements such as refrigerated warehouses.

For this reason, a possible 4th generation glucose biosensors may be, instead, a chemosensor. That is, a glucose sensor that does not use a biological receptor at all. However, an artificial receptor with a sensitivity and selectivity comparable to existing enzymes has not been found yet.

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