Friday, January 30, 2015

The Magical Tattoo - yeah, sure.

The "magic tattoo" strikes again...  

For a couple of weeks now, diabetics forums all over the world have been buzzing with excitement over that amazing new "glucose sensing tattoo". Some people seem ready to buy it right here, right now. Apparently, they don't read further than the headlines... (Universities love to make headlines with glucose sensing tattoos - see here for a 2009 release, that one based on a different technology)

While the full article isn't available on-line anymore, the abstract is here

Let me give you a hint of what is to come by showing you the functionally equivalent part of the Libre FGM sensor. See those tiny metallic circles in the center? Yes, that's it. Add a very small subcutaneous wire and you have also replaced the "gel" under the tattoo...

 How does the tattoo measure glucose?

The tattoo attempts to measure glucose by using the well known glucose oxydase reaction. This reaction has been used to measure blood glucose levels since at least 1957 (here) and is what your blood glucose meter probably uses although, for the sake of completeness, I should mention that the glucose deshydrogenase reaction has its supporters (here). This is also the reaction at the core of our current CGMs systems. It generates a very small electrical current - a flow of electrons - proportional to the amount of the glucose it oxydizes. That flow of electrons is then measured by an amperometric sensor and finally correlated with glucose concentrations. So far, so good: the technology is proven and has slowly matured over the last 50-60 years. Proven, but hardly innovative.

Where does the glucose come from?

When you measure your blood glucose level with a glucometer, the answer is obvious: glucose-oxydase reacts with the glucose present in the blood drop sample. A sub-cutaneous CGM measures the glucose present in the interstitial fluid, the liquid that makes humans soft and squishy. The glucose concentration in the interstitial fluid depends, with a few minutes delay, on the glucose concentration in blood. The extremely complex transfer process is summarized here. It is possibly one of the hottest current research topic since a full understanding of that system is essential to the development of effective artificial pancreases.

But how does the tattoo get its glucose? Unfortunately, humans aren't renowned for their glucose sweating abilities. The molecule has to be forcefully extracted to the surface of the skin from the interstitial tissue. The skin is a biological membrane whose goal is to keep essential molecules and liquids inside our bodies. The technique used by the tattoo is called reverse iontophoresis. It is a more recent innovation than the glucose-oxydase reaction, but still dating back to 1995 at least (here). In fact, products attempting to measure glucose non-invasively through reverse electrophoresis have already been developed, already been approved by the FDA and already been withdrawn.  Well, they had annoying cutaneous side effects, were slow and unreliable. This is probably because they failed commercially (you can read part of the ill-fated Glucowatch story here).

Forcing a glucose molecule through the skin is never going to be an easy task. While the University commentary mentioned the Glucowatch noting that the new method used less intense currents, this was of course ignored in the press coverage.

So, no progress here either. Trans cutaneous measure as implemented here is definitely a giant step back if one aims for a closed loop system.

What did the tattoo achieve?

Connected to a lab power supply, the tattoo took ten minutes to extract glucose from under the skin. That glucose reacted with a glucose-oxydase prepared tattoo (as it was expected to) and did not react with a blank control tattoo. The amperometric sensor showed a current increase that was correlated with the absorption of glucose (a soft drink) after some delay (as it was expected to).

That's it. As the author noted, some work remains. (insert favorite emoticon here)

But I still want one!!!

Yes, the tattoo looks so cool. So you might want one anyway. Anything else you need to get up and running in addition to a glucose-oxydase gel and the tattoo?
  • a laboratory power supply
  • an amperometer
  • wires
  • a computer
  • a thermometer
  • a mathematica license or the ability to develop your own methods in numpy
  • a keen sense of observation to correlate measured values with glucose values.
Please note that current CGM include all of this in small boxes that are a bit bigger than a couple of coins.

You'll be facing the following additional challenges (incomplete list)
  • skin is not a constant
  • you'll be adding a 10 minutes reverse intophoresis delay to the already present 5-6 mins (best case) blood glucose - interstitial glucose delay
  • your blood glucose concentration will change while you measure
  • your interstitial glucose concentration will change because you are actively driving molecules to and through the skin
  • you'll be dealing with concentrations two orders of magnitude lower than what can be observed invasively.
  • consequently, you will suffer from an accuracy that will be intrinsically limited by the signal to noise ratio of the whole system
What will you gain?
  • you will avoid a CGM insertion every two weeks and a couple a finger pricks per day.
While you can't expect much from the Internet mainstream press, I was really surprised by the very superficial coverage of the tattoo on many diabetic centric sites. I would have expected better. Maybe their role isn't to inform in depth but rather to deliver a bit of optimistic news ("within five years....") now and then to keep us going. Maybe it is better not to know...

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