Nanoneedle: can impedance measures really indicate the benefits of a drug?

[Tallman]

So the Nanoneedle electrodes measure the impedance of the blood plasma and everything that’s in it, right? Before the measurements are commenced, NaCl is added to the plasma as a stressor. In the control sample with plasma from a healthy person, impedance is unchanged over time. In the blood plasma from an me/cfs patient, the impedance increases, suggesting that the cells can’t hinder the salt from osmosing through its membrane. Therefore the conductivity in the solution is decreased since the salt is being absorbed.

However, when certain drugs or substances (such ss SS-31 and Copaxone) are added to the me/cfs blood sample, the impedance is normalized back to the initial value. This has been interpreted as an indicative that the drug helps restore the normal function of the blood cells, enabling them to transport the salt back through the membrane and out into the blood plasma.

But what if it’s just the drugs having good conductive properties? So that the impedance drops back to normal thanks to the drug working as an electrical shortcut, regardless of the cell’s success or failure to rid the NaCl? E.g. Copaxone contains some kind of acetate salts which would make it a good conductor. I would very much like to know if and how Davis and his team have been reasoning around this.

 

[leokitten]

IMO the probability that the nanoneedle will be able to translate results directly to human efficacy is low.

To me it’s currently still very much in the phase of a basic research tool to try to understand some part of ME pathophysiology. Hopefully it will eventually be able to become an FDA approved ME clinical diagnostic tool, but that’s still a very long ways off.

But to become a translatable clinical drug discovery tool all by itself is not likely. Maybe it will become some sort of initial drug screening tool (similar to Tecan high-throughout drug screening robots pharma has, but low throughout) and positive hits will then undergo the research process of drug development. So it won’t leapfrog any of those steps unless it’s an already FDA approved drug.

If it’s an FDA approved drug for another condition that is very expensive, then it will still have to go through many hurdles and successful clinical trials to get ME FDA approval before insurance will pay for it.

 

[frozenborderline]

So the Nanoneedle electrodes measure the impedance of the blood plasma and everything that’s in it, right? Before the measurements are commenced, NaCl is added to the plasma as a stressor. In the control sample with plasma from a healthy person, impedance is unchanged over time. In the blood plasma from an me/cfs patient, the impedance increases, suggesting that the cells can’t hinder the salt from osmosing through its membrane. Therefore the conductivity in the solution is decreased since the salt is being absorbed.

However, when certain drugs or substances (such ss SS-31 and Copaxone) are added to the me/cfs blood sample, the impedance is normalized back to the initial value. This has been interpreted as an indicative that the drug helps restore the normal function of the blood cells, enabling them to transport the salt back through the membrane and out into the blood plasma.

But what if it’s just the drugs having good conductive properties? So that the impedance drops back to normal thanks to the drug working as an electrical shortcut, regardless of the cell’s success or failure to rid the NaCl? E.g. Copaxone contains some kind of acetate salts which would make it a good conductor. I would very much like to know if and how Davis and his team have been reasoning around this.

That's a great question and I think the correct answer is nobody really knows. On paper it would seem odd if that very strong statistical signal that showed up in me/cfs patients but not controls was something that didntncorrelate to disease at all but weirder things have happened.

I do worry that Davis has gotten so hyped up about a result that's very impressive on paper he hasn't thought to really try and replicate it in other cell types or things that might turn out to disprove it. I mean , its just pbmcs or some type of useless white blood cell that isn't really representative of all cells , but is just somehow easier to use in the lab... and he hasn't tried it with other cell types, correct?

On paper, it looks amazing to get that level of separation from controls but without testing it in other cell types or figuring out what it correlates to in vivo it seems like ron may be not trying to disprove his theory hard enough.

 

[Hip]

Before the measurements are commenced, NaCl is added to the plasma as a stressor. In the control sample with plasma from a healthy person, impedance is unchanged over time.

In the blood plasma from an me/cfs patient, the impedance increases, suggesting that the cells can’t hinder the salt from osmosing through its membrane. Therefore the conductivity in the solution is decreased since the salt is being absorbed.

I am not sure if the absorption of salt into the cells explains the change in impedance.


When one talks about impedance, this involves alternating current, and Davis is using a 15 kHz alternating current. This I believe will tend to measure the capacitance of the cell.

In an electric circuit, a capacitor consists of two electrically conducting plates placed close together, but separated by an insulator. Direct current cannot flow through a capacitor (from one plate to another), because it is blocked by the insulator in between. But an alternative current can flow across a capacitor. The higher the capacitance, the more current will flow.

In a cell, a capacitor is naturally formed by the lipid membrane, which is an insulator, and the extracellular and intracellular fluids on either side, which form the two conductors.

So I think the 15 kHz alternating current would probably be measuring changes in the capacitance of a cell.


(I used to be interested in electronics as a hobby years ago).

 

[wigglethemouse]

The electrodes are only 30nm apart so it could be resistance. From the paper

The nanometer-sized sensing region of the sensor consists of a 30-nm-thin oxide layer sandwiched between two 100-nm-thin gold layers. The top protective oxide layer is intended to prevent the exposure of the top conductive electrodes to the solutions. There is a thermally grown oxide layer underneath the bottom electrodes to electrically insulate the sensors from the substrate. Each sensor's width is ~3um 5um.

I seem to remember that they found that the real component of the impedance Zre, aka the resistance, was the main factor. Ahhh, that is the case. I wrote about it on s4me and included details from the paper
https://www.s4me.info/threads/a-nan...dyarpour-davis-et-al.9284/page-23#post-262104

 

[Hip]

I seem to remember that they found that the real component of the impedance Zre, aka the resistance, was the main factor. Ahhh, that is the case. I wrote about it on s4me and included details from the paper
https://www.s4me.info/threads/a-nan...dyarpour-davis-et-al.9284/page-23#post-262104

Interesting. But then if they are measuring the resistance component of the impedance, rather than the capacitive reactance component, why not use a direct current? If the are measuring DC resistance, the purpose of the 15 kHz alternating current is not clear.

 

[wigglethemouse]

But then if they are measuring the resistance component of the impedance, rather than the capacitive reactance component, why not use a direct current?

That would be an interesting experiment. But it is possible there may still be a series capacitive component that at 15kHz has a relatively small value compared to the resistive component at 15kHz. At DC = 0kHz, the series capaciance component if there is one could be blocking

If you look at the literature there are a fair number of papers measuring cellular impedance. This is a list of studies using one particular integrated circuit that was designed to measure cellular impedance. There are other scientists using 15kHz too. Seems to be a sweet spot measurement point.

Source : http://journals.pan.pl/dlibra/publication/104293/edition/90297/content