Evolution of Electron Mediators

Evolution of Electron Mediators in [Diabetic Test Strips](/sell-diabetic-supplies/)

A mediator is the small molecule that carries electrons from the enzyme on a test strip to its electrode, where the meter reads them as a current [1]. Oxygen did that job in the first enzyme sensors of the 1960s, and a ferrocene compound went into the first electrochemical home meter in 1987 [1]. Since then, FDA records and journal papers have tied four more mediators to specific strips: ferricyanide, osmium, ruthenium and phenanthroline quinone [2] [3] [4] [5].

Below, each step is dated by the product launch or FDA record that pins it down. That isn't always the year a chemistry was first used, and we say where the paper trail runs out. For how the mediators work and compare, see our articles on electron mediator technologies and ferrocene vs. osmium vs. ruthenium.

1962 to the early 1980s: oxygen carries the electrons

Clark and Lyons proposed the glucose biosensor in 1962. Their design laid a thin layer of the enzyme glucose oxidase (GOx) over an oxygen electrode, and the drop in oxygen tracked the amount of glucose [1]. Updike and Hicks later made the idea more practical by trapping GOx in a gel on the oxygen electrode [1]. In these first-generation sensors oxygen was the electron carrier, and later designs measured the hydrogen peroxide the reaction produced [1].

Two weaknesses pushed researchers toward something else. Reading hydrogen peroxide took a high electrode voltage, which also picked up ascorbic acid (vitamin C), uric acid and some drugs. Oxygen also dissolves poorly in body fluids, so its level swings from sample to sample, a problem known as the "oxygen deficit" [1].

Here's what surprised us: home testing skipped this stage. The first blood glucose strip, Dextrostix, was available from 1965 and was read by its color change. The first meter, the Ames Reflectance Meter of 1971, was a reflectometer that read color, not an electrochemical sensor [1].

1984 to 1987: ferrocene reaches a home meter

Mediated sensors, which biosensor researchers call the second generation, swapped oxygen for a synthetic electron carrier that the electrode recycles after each trip [1]. In 1984 Cass and colleagues published a ferrocene-mediated enzyme electrode for measuring glucose [6]. Three years later MediSense launched the ExacTech, a pen-sized meter and the first electrochemical blood glucose monitor for self-testing. It paired GDH-PQQ (glucose dehydrogenase with a pyrroloquinoline quinone cofactor) with a ferrocene derivative [1].

Writing in 2010, Yoo and Lee said most commercial glucose biosensors still worked much like the ExacTech, and that various self-monitoring strips were based on ferrocene or ferricyanide mediators [1].

2000: osmium in Abbott's FreeStyle strips

FDA's 510(k) database lists a clearance for the FreeStyle Blood Glucose Monitoring System decided on January 14, 2000, under number K992684 [7]. The system came from TheraSense, now part of Abbott Diabetes Care, and became available that year [3]. Its developers later described the chemistry: GDH with an osmium (Os2+/3+) complex as the mediator, in a strip holding 300 nanoliters of blood that counts total electric charge rather than measuring current at one moment [3]. The enzyme changed over the years, from GDH-PQQ at launch to FAD-dependent glucose dehydrogenase (GDH-FAD) [3].

FDA's 2010 decision summary for FreeStyle Lite strips records that enzyme switch, but it says only that electrons pass "via a co-factor and mediator" [8]. The osmium step is dated by the product launch, then. We couldn't confirm from public FDA records that FreeStyle strips sold as of October 2026 use the same complex.

2011 and 2015: ferricyanide in FDA decision summaries

Ferricyanide is the mediator FDA records name most plainly, and a 2017 study called potassium ferricyanide the most common mediator in commercial strips [9]. LifeScan's OneTouch Verio clearance, decided February 11, 2011, lists 2 units of GDH-FAD and 41 µg of potassium ferricyanide per strip [2]. The OneTouch Ultra Plus Flex strips, cleared December 14, 2015, list the same enzyme and the same 41 µg [10].

Those dates mark when we found ferricyanide written into a decision summary, not when it first went onto a strip. Yoo and Lee were already pairing it with ferrocene in 2010 [1], and we didn't find a primary record that dates the first ferricyanide strip.

2013 to 2014: ruthenium arrives in True Metrix, then leaves

The clearest ruthenium entry in FDA's files has both a start and an end. FDA cleared Nipro Diagnostics' True Metrix system on April 24, 2013, and that summary lists GDH-FAD and "mediators" without naming them [11]. On August 1, 2014, FDA cleared a change whose stated purpose was to move the strip "from hexaammineruthenium (III) and Meldola's Blue to Potassium ferricyanide (III)" [4]. The ruthenium version's FDA paper trail runs about 15 months.

Ruthenium didn't disappear with it. In 2017 Loew and colleagues described hexaammineruthenium(III) chloride as a mediator gaining attention for commercial strips, and wrote that some commercial GOx strips already used it [9].

As of October 2026, an FDA safety communication recommends that everyone using Trividia Health's True Metrix meters move to another way of testing when possible. The cause is an E-5 error code that means both a very high reading and a strip error, a software and labeling problem rather than a chemistry one [12]. Choosing a replacement is a decision to make with your care team.

Phenanthroline quinone in Abbott's Precision strips

The last name on this list is the hardest to date. A 2021 study in Japan used Abbott's FreeStyle Precision strips, read on the FreeStyle Libre reader, as its fingerstick reference. The authors described those strips as using glucose dehydrogenase, nicotinamide adenine dinucleotide (NAD) and phenanthroline quinone [5]. We didn't find a primary record of when phenanthroline quinone first went into a strip.

The US record is thinner. FDA's 2017 summary for FreeStyle Precision Neo strips, which extended them to the meter built into the FreeStyle Libre reader, names GDH-NAD as the enzyme and says electrons travel "via a co-factor and mediator" without naming the mediator [13]. We couldn't confirm that US Precision Neo strips use the same mediator as the strips in the Japanese study.

One detail in that 2017 summary ties the end of this timeline to its start. It refers to "MediSense Glucose and Ketone Control Solutions" [13], carrying the name of the company that launched the ferrocene-based ExacTech in 1987 [1].

Mediator-free strips: not in the records we read

Yoo and Lee describe a third generation of sensors that drops the mediator altogether and passes electrons straight from the enzyme to the electrode, an approach they credit with better selectivity [1]. Our article on direct electron transfer covers that research. None of the six FDA strip summaries we read for this timeline describes a mediator-free strip; every one names or mentions a mediator [2] [4] [8] [10] [11] [13].

That points to the limit of this history. In our reading, the FDA decision summary is the best public record of a strip's mediator, and for FreeStyle Lite and FreeStyle Precision Neo even that says only "mediator" [8] [13].