Researchers are developing a programmable lab on a chip

Breaking new ground 10. may 2022 3 min Professor, Section Head and Deputy Director Jan Madsen, Professor Winnie Edith Svendsen Written by Kristian Sjøgren

Researchers can move tiny droplets of fluid on a minuscule biochip to carry out microscale experiments, including cell cloning experiments. The researchers are developing a lab-on-a-chip (biochip) technological platform (cyber-fluidic) that can eventually perform experiments fully automated, with minimal assistance from people.

Researchers from the Technical University of Denmark have developed a lab-on-a-chip (biochip) that works by moving droplets on a biochip in microscale experiments.

In various scenarios, the cyber-fluidic platform, no larger than a hand, can replace traditional experiments that have previously required researchers to move larger volumes of liquid in test tubes and flasks.

Biochips can be used to conduct experiments at the smallest possible scale to conserve reagents and to increase the reaction rate. They can also be used for diagnostics: for example, these biochips can test samples for SARS-CoV-19.

The idea behind biochips is that they must be programmable and perform specific operations and experiments independently. To support this, the researchers have further developed the underlying computer platform.

“Our research focuses on explaining the whole design concept behind making such a system that must be configurable and reconfigurable. We are thus trying to apply what we have learned from the computer revolution in developing biochip,” explains Jan Madsen, Professor, Section Head and Deputy Director, Department of Applied Mathematics and Computer Science (DTU Compute), Technical University of Denmark, Kongens Lyngby.

The research, which has been published in Micromachines, was carried out by a cross-disciplinary team of researchers from DTU Compute, DTU Bioengineering and DTU Biosustain (the Novo Nordisk Foundation Center for Biosustainability).

Experiments at microscale

The biochip uses a technique called digital microfluidics, which enables the manipulation of individual droplets on a flat surface.

By moving the droplets and mixing the relevant reagents, researchers can perform microscale experiments that are identical to those performed in a full-scale laboratory.

For example, Jan Madsen and colleagues are striving to demonstrate that full-cell cloning can be performed on a microfluidic biochip instead of in test tubes, the normal procedure today.

The researchers can use polymerase chain reaction (PCR) on a biochip, where the DNA fragments are contained in a droplet that is alternately heated and cooled. This generates sufficient DNA from which the desired fragments are selected and transferred into a living cell that can thereby acquire new properties.

Cell cloning in biochips can be useful for developing new yeast cells for beer production or for developing new treatments for cancer. However, this process requires many operations of mixing droplets and splitting them into several smaller droplets.

“These are absolutely fundamental processes that can be useful to perform at microscale in a process that can run fully automatically without laboratory technicians. The whole process usually carried out in a large laboratory can instead be carried out in a small lab device,” says Jan Madsen.

System performs experiments independently

The biochip that Jan Madsen and colleagues have built is fulfilling a longstanding need for a completely new way of performing experiments.

However, the problem is making the device easier to use.

The challenge is making the microfluidic device dynamically programmable so that it cannot only autonomously follow predetermined instructions but also respond dynamically to what happens to the droplets.

This might involve performing a task at a certain temperature or based on a specific target concentration of a reagent.

“At DTU Compute, we are developing the computer system and ensuring that the biochip can enable the user operating the device to programme it like a computer. The user should be able to tell the device what to do without necessarily knowing the detailed functions that will carry out the task. The computer system must then carry this out,” explains Jan Madsen.

Needs to be programmable

Jan Madsen and colleagues are attempting to take the computer system to the next level.

For example, the researchers can already get the various steps in the cell-cloning process to run fully automatically in the biochip, but problems arise when the whole process must run from start to finish over several hours. The researchers still need to tackle the last obstacles.

Jan Madsen explains that the research also involves establishing a common application-agnostic microfluidic architecture that enables the biochip to become an integrated part of a highly reconfigurable system to mix ingredients, change the temperature and carry out other actions.

“For example, we want to be able to instruct the system to take certain quantities of liquids A and B and mix them for 12 minutes at 55°C. The computer then needs to translate this abstract description into a sequence of basic operations that the platform makes available. In addition, the system must be able to do several things at the same time,” says Jan Madsen.

Obstacles to be overcome

Jan Madsen explains that the researchers have made progress after developing the system for many years but have also encountered obstacles.

For example, moving droplets of water is relatively easy, but moving droplets of biological materials without leaving residue that could contaminate other droplets is far more complex.

Although the researchers are making progress in solving this problem, another challenge is that tiny droplets evaporate easily when heated.

“Using such small volumes poses challenges but also provides benefits. We can use cameras and sensors to monitor where the materials are. We can also conditionally execute laboratory protocols, with the biochip performing operations depending on what happens in the experiment, including in the biochemical reactions inside the droplet itself,” concludes Jan Madsen.

BiowareCFP: an application-agnostic modular reconfigurable cyber-fluidic platform” has been published in Micromachines. In 2019, the Novo Nordisk Foundation awarded a grant to co-author Winnie E. Svendsen for the project MagicBox: Digital Microfluidics Platform for Strain Development in Biotechnology. The Copenhagen Center for Health Technology (CACHET) also supported the research.

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