Mediator Chemistry: Ferrocene vs. Osmium vs. Ruthenium

Mediator Chemistry: Ferrocene vs. Osmium vs. Ruthenium

A mediator is the small molecule in a test strip that carries electrons from the enzyme to the electrode, where the meter reads them as a signal [1]. Of the three in this title, ferrocene went into the first electrochemical home meter, osmium went into Abbott's FreeStyle strips, and ruthenium is the one a 2017 study described as gaining attention [1] [2] [3]. None of them is the most common choice, though. That distinction belongs to a fourth mediator, ferricyanide [2].

What a mediator has to do

The enzyme on a strip, either glucose oxidase (GOx) or glucose dehydrogenase (GDH), pulls electrons off glucose. Early sensors relied on oxygen to carry those electrons away. Mediators replaced oxygen: the enzyme hands electrons to the mediator, and the mediator gives them up at the electrode, producing the current the meter measures [1]. Our enzyme chemistry article covers the enzyme side of that handoff.

A 2017 paper lists what a good mediator needs. It should react quickly with the enzyme and pass electrons to the electrode easily. It should also stay stable in both its oxidized and reduced forms and leave oxygen alone [2].

The property that matters most for accuracy is the operating potential, meaning the voltage the meter applies to the strip. Any substance in blood that reacts at that voltage donates electrons that didn't come from glucose, which pushes the reading falsely high [1]. A mediator that works at a lower potential lets the meter use a lower voltage, and a lower operating potential generally means fewer interferences [2].

The four mediators, one at a time

Ferrocene

Ferrocenes meet every item on that wish list: they don't react with oxygen, they're stable in both forms, and they behave the same across pH [1]. The first ferrocene-mediated amperometric glucose sensor was reported in 1984. Three years later MediSense launched the ExacTech, the first electrochemical meter for home testing, which paired GDH-PQQ with a ferrocene derivative [1]. A 2010 review said various self-monitoring strips were based on either ferrocene or ferricyanide [1]. We didn't find a current FDA decision summary that names ferrocene for a specific strip.

Osmium

Osmium shows up as a complex, a metal atom held inside a larger molecule. Abbott's FreeStyle system, available from 2000, used GDH with an Os(2+/3+) redox complex in a strip that held just 300 nanoliters of blood [3]. That strip is a coulometer, built between two printed electrodes with a tightly controlled blood volume, so it measures electric charge rather than current [3]. Our article on coulometry vs. amperometry explains the difference.

Here's what surprised us about why osmium was chosen. FreeStyle's two printed electrodes face each other only 50 micrometers apart, close enough that a mediator could shuttle electrons back and forth between them and corrupt the count [3]. The developers picked an osmium complex with a formal potential between 0.0 and -0.2 V against the facing silver/silver chloride electrode, which makes that shuttle current "virtually impossible" [3]. The same team's FreeStyle Navigator CGM went a step further and bound its osmium complex to a polymer that "wires" the enzyme to the electrode [3].

Ruthenium

The ruthenium mediator in strips is hexaammineruthenium(III) chloride. It is easy to obtain, stable in both forms and soluble in water [2]. Its redox potential is about -0.11 V against silver/silver chloride, compared with +0.23 V for ferricyanide, so strips built on it can run at a lower operating potential. Their packaging requirements are also less stringent [2].

Ruthenium has limits. In that 2017 lab study, it accepted no electrons from a fungal FAD-GDH, only from a bacterial one. With the bacterial enzyme it also showed more bias from maltose, a sugar found in some intravenous drug preparations: +39% at 20 mM maltose, against +18% for ferricyanide at the same level [2]. A lower potential helps, but the enzyme and mediator have to suit each other.

Ferricyanide

Ferricyanide is the most common mediator in commercial strips, according to the same study. Its electron transfer is reversible, and chemists use the same redox pair as a standard probe when testing electrodes. The catch is storage: ferricyanide strips need special packaging that keeps them dry and dark [2].

Where oxygen fits

Oxygen sensitivity turns out to be mostly an enzyme question. When the enzyme is GOx, oxygen from red blood cells can compete with the mediator for electrons [1]. GDH doesn't react with oxygen, which is one reason it suits mediated strips [2].

A real strip that changed mediators

One FDA record shows these trade-offs in a product. In 2014 the FDA cleared a change to True Metrix strips that replaced hexaammineruthenium(III) and Meldola's Blue with potassium ferricyanide(III) [4]. The predicate strip listed xylose as an interferent. The new strip listed xylose, uric acid and ascorbic acid, and the decision summary calls those additions "the result of a mediator change" [4]. Moving to the higher-potential mediator put two more substances on the interference list, which is what the chemistry predicts [2].

True Metrix meters are now sold by Trividia Health. As of October 2026, an FDA safety communication about the meters' E-5 error code, a software and labeling issue rather than a chemistry one, recommends that users move to another testing method when possible [5]. Whether and how to switch is a decision to make with your care team.

Which current strips name their mediator

Most FDA decision summaries we read don't name it. The FreeStyle Lite summary says only that electrons pass "via a co-factor and mediator" in a coulometric strip [6]. The Contour Next One summary describes FAD-GDH and "an electron mediator" [7]. The Accu-Chek Guide summary names the enzyme and the AC and DC signals the meter reads, but no mediator [8].

For FreeStyle strips, the developers' 2010 account of an osmium mediator is the closest public source we found [3]. We couldn't confirm that today's FreeStyle Lite strips use the same complex. The mediator rarely appears on a box. Its effects show up instead in two places on the labeling: the list of interfering substances and the storage instructions [2] [4].