New window on cells

‘We are developing a technology that will open up a completely new window on living cells,’ says Harrie Verhoeven, cell biologist at Wageningen University. ‘This is a complimentary form of microscopy that makes it possible to image previously unexplored properties of cells.’ Together with Serge Lemay and Cecilia Laborde from the University of Twente, he is investigating the possibilities of a new chip that was developed by Frans Widdershoven from semiconductor manufacturer NXP.

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Laborde, Lemay, Verhoeven and Widdershoven recently published an article in Nature Nanotechnology disclosing the first, highly promising measurements of a new chip that uses high frequencies to measure small electrical signals in liquids. One of the possibilities the researchers demonstrated was that with this chip you could see how certain aggressive breast cancer tumour cells move, which is an important characteristic for the extent to which they can spread. This provides possibilities for testing the effect of new medicines.

Chip measures small electrical signals from cells

‘At NXP, we had our own biosensor group until the end of 2011. Within this group, we had developed a chip that could measure small electrical signals that originate from cells in liquids. Those signals are a measure for the activity and nature of the cells. Initially, this was mainly a research chip: we wanted to see what we could do with it. To this end, we sought collaboration with university groups via NanoNextNL,’ says Frans Widdershoven of semiconductor manufacturer NXP.

Standard technology as the basis

The chip consists of 256 rows and 256 columns of nanoelectrodes on a standard CMOS (Complementary Metal Oxide Semiconductor) chip. CMOS technology is commonly used in devices such as smartphones, tablets and computers, which derive their calculating power and communication possibilities from these chips. It is a tried and tested technology that uses very little electrical current.

Following cancer cells

Lemay, Laborde and Verhoeven investigated various applications for the chip. For example, the chip appeared to be suitable for detecting the movement of micrometre-sized particles and living cells. You can follow how a particle moves, whether it is growing or whether it is binding to something. For example, during an initial exploratory study, researchers from Wageningen University managed to follow in real time how cancer cells in a growth medium attached to the chip. ‘We examined several different types of tumour cells and we could very clearly distinguish which cells were the most mobile. And that mobility is a measure of how aggressive such a tumour is and how easily it spreads,’ says Verhoeven.

You can easily add various medicines to a tumour cell and then use the chip to follow what the results are in real-time.

Drug research

This has consequences for drug research. You can easily add various medicines to a tumour cell and then use the chip to follow what the results are in real-time. ‘Tumour cells differ from normal cells in several aspects. One of the differences lies in their energy metabolism,’ explains Verhoeven. ‘We are increasingly moving towards treatments that specifically target the energy metabolism. I expect that we will be able to make very good use of this chip to visualise the consequences of those treatments on such a tumour cell.’

Growing breast tumours

One of the main advantages of the chip compared to other detection systems is its ability to measure in saline environments. In other measurement systems, the salt, which is found in bodily fluids for example, disrupts the measurements. This means that with this chip, you can study cells in their natural environment. ‘For example, we have studied breast tumour cells in a growth medium,’ says Widdershoven. ‘You are then literally able to see these cells grow.’
The fact that you do not have to pre-treat the cells for this technique is a big advantage, says Verhoeven. ‘For the majority of imaging techniques, you need to add fluorescent substances, or manipulate the cells in another way. This means you cause disruptions in the cell. The question then remains to what extent the behaviour you see actually matches the natural behaviour of such a biological system.’

The new technology has many advantages. CMOS technology is cheap and you can use it to process large quantities of data. You do not need any lenses or light sources, which means you do not need to purchase an expensive microscope. Furthermore, the technology is easy to scale up.

Cheap and plentiful at the same time

The new technology has many advantages, says Widdershoven. ‘CMOS technology is cheap and you can use it to process large quantities of data. You do not need any lenses or light sources, which means you do not need to purchase an expensive microscope. Furthermore, the technology is easy to scale up.’ That is a most welcome improvement for cell biologists like Verhoeven. ‘At present, we can only examine individual cells if we want to know something about cell membranes. With this chip, you can examine hundreds or thousands simultaneously.’

Seeking the boundaries

Meanwhile, Lemay and Laborde continue exploring the boundaries of the technology. ‘In collaboration with Wageningen University, we are looking at what we can say about cell dynamics based on measurements with the chip, for example,’ says Laborde. ‘We will also investigate how sensitive the sensor is. One of the aspects we want to investigate is what the limits of the measurement technique are. What are the smallest objects we can still see?’ adds Lemay. ‘Electrodes are becoming increasingly smaller. The smaller the electrodes, the closer you can place them next to each other and therefore the smaller the particles you can see,’ says Widdershoven. ‘With this technology, it should be fairly simple to see objects that are smaller than what you could ever render visible using a light microscope,’ adds Verhoeven.
‘And with higher measurement frequencies, we can more easily see through cell walls or in liquids with a high salt concentration. At present, the highest frequency is still limited by the time that a row of transistors on the chip needs to be able to switch simultaneously. However, that speed is increasing in newer CMOS generations. Ultimately, this speed could well end up in the gigahertz range. That would open up new possibilities to extensively study inside and outside of living cells and small particles such as viruses,’ says Lemay.

Seeing a cell communicate

‘These are exciting times for biology,’ says Verhoeven. ‘We have had to invest some time in discovering exactly how we should interpret the electrical signals so that these can be translated into cell behaviour. Now that we have mastered that, I can see many possible applications for this technology. I think it should be possible to use this technique to follow how the ion channels in a nerve cell open and close in real time. You would then be able to see how such a cell communicates with its environment. That would really be spectacular.’