Investigators at the University of Chicago have developed a droplet-based microfluidic device that allows them to stimulate, record, and analyze molecular signals with high temporal and spatial resolution.
Previous techniques for stimulating and measuring chemical reactions in cells relied on laminar flow, which allows the chemicals under investigation to intermingle and disperse, making them difficult to control and measure.
But the Chicago team’s technology, which they call the chemistrode, traps the compounds in aqueous droplets and suspends them in a fluorocarbon carrier fluid. This keeps the compound-laden droplets intact, allowing a controlled stream of stimulating chemicals to enter on one end of the device, and a steady stream of distinct resultant chemicals to be captured on the other end.
These resultant signals can be injected with additional reagents and analyzed in parallel offline by multiple, independent techniques, such as fluorescence microscopy and fluorescence correlation microscopy. When recombined, these analyses provide a time-resolved chemical record of a cell’s response to stimulation.
The researchers’ work was published online last week in the Proceedings of the National Academy of Science, and will appear in this week’s print edition of the journal.
Delai Chen, a graduate student in the department of chemistry at the University of Chicago, spoke with CBA News this week about the chemistrode and its application in screening compounds in drug discovery.
Can you give me a little background on this work?
We basically wanted to develop a tool to be able to perturb chemical systems with high temporal resolution. We know that microelectrodes enable the stimulation and recording of electrical signals at very high temporal resolution.
Our lab has pioneered the use of droplet-based microfluidics. We use microfluidic droplets to transport a chemical. Then we had this idea of using droplets to design this tool, which we call a chemistrode.
How exactly does the chemistrode technology work?
We have a capillary in which there is an array of droplets. Every droplet can contain different chemicals. When we flow these droplets over the substrate containing the cells, these droplets will contact with the surface, so the cells are stimulated by the chemicals in the droplet.
If the cells release something as a response to these stimuli, these chemicals can also go into the droplets and get carried into the receiving capillary, and we can take measurements with these droplets.
This was not possible before, because in the past, people did not use droplets, they had just one phase, just one liquid, the aqueous liquid.
If we have pulse responses released from the cells, these pulses will become broader over time, because the molecules will diffuse, and when they are transported, the pulse also broadens. Previously, people could not get high temporal resolution from their experiments because the pulses became broader.
Now, because the pulses are captured in individual droplets, you can store the temporal information. The pulse will not have become broader. You can still keep the temporal information. You can use all kinds of analytical controls to analyze the droplets.
The use of droplets is the key to our method.
How would this technology be used to screen compound libraries in drug discovery?
We can deliver a drug and deliver it to the cell surface, and watch the timing of the cellular response. For example, if we stimulate the cells with a compound, compound A, what is the sequence of chemicals released from the cell? Also, some responses may not happen until we stimulate the cell first with chemical A, then with chemical B, and then with chemical C. We can deliver a sequence of stimuli to the surface. That is our biggest advantage.
What is the next step in this work?
We want to use the chemistrode to study, for example, complex reaction networks. We have a couple of other ideas too, but this is the one that we are going to do next.
Is this chemistrode technology something you plan to license or commercialize?
Not yet. I think that this will be a research tool. We are very far way from commercialization.