Jan Provoost Science Editor imec

Researchers Use Chip Technology to Create Cell Culturing with Integrated Sensors

Imagine researchers could grow human cells in vitro, mimic their behavior in miniature artificial organs, and test their every whim when they confront them with hundreds of candidate drugs. Imagine they could do that with cells from people with a specific disease to go on a targeted hunt for new cures, or with your very own cells, to see which treatments best fit you.

It’s an enticing idea that is being developed around the world into what could become a paradigm shift in drug discovery. Dries Braeken, research team leader at the R&D center imec, and his team believe they hold one of the keys. With silicon technology, they say, it is possible to make an ideal housing for out-of-body organs with integrated multiparameter sensoring, microfluidics, and intelligence to boot—not to mention the possibility of cost-effective mass production.

A Mouse is Not a Human–-and One Human is Not You

At this moment, the workhorse techniques used to discover and develop drugs are in vitro testing on immortalized cell lines and in vivo testing on animals. However, these tests too often fail to predict what will happen once drugs are administered to large groups of genetically diverse people.

One of the major concerns is the effect of a new candidate molecule on heart cells. These should keep on contracting in a very precise and coordinated way if the heart is to pump blood efficiently. Even when drugs affect only a small change in the rhythm or vigor of that contraction, the heart may stop pumping. A second organ easily impacted by new drugs is the liver, otherwise known as the body’s chemical plant.

One solution would be to create a model of the heart or liver (or both) outside the body by culturing a monolayer of synchronously contracting heart cells in a petri dish, and then, very precisely and over time monitor what happens when candidate drugs are added. The advent of induced pluripotent stem cell (iPSC) technology—in which skin cells, for example, can be taken from individual patients and turned into any cell type—has given this idea a boost.

The petri dish, however, may not be the best environment for our out-of-body heart. The cells find themselves in a one-dimensional flatland, in which they tend to grow randomly, with no pressures and three-dimensional queues from neighboring cells to guide them. As small, cheap, and practical as it is, a petri dish has to be studied with expensive large microscopes operated by technicians or with chemical and mechanical tests that often destroy the sample. 

If We Could Put it All On a Chip

Eight years ago, researchers at imec started experimenting with biocompatible multielectrode arrays. These are chips with a surface consisting of thousands of microsized, three-dimensional electrodes.

“We have learned to create chip surfaces that cells love, attaching and aligning themselves around these topographical structures,” says Dries Braeken. “With these chips, we can now measure the electrical activity in cell cultures, even zooming in on single cells. It’s a major step forward compared to patch-clamping, which requires lab technicians with a good eye and a steady hand. But that is not all; with the cellular monolayer growing on our chip surface, we can even look at the propagation of the electrical signals between neighboring cells as they communicate.”

The team at imec is now experimenting with advanced texturing of the chip surfaces, so that the cells may grow in a more natural environment. Braeken calls it a 2.5D environment. “On a flat surface, cells tend to sag randomly, in fact reinventing themselves in an unnatural environment. With the topography that we add, they feel the pressure and presence of neighboring cells,” says Braeken. “Their shape is much more what you would see in an organ or tissue.  Making micrometer-precise structures on large substrates is a capability not available to most biolabs. For a chipmaker it is just another process that can be repeated extremely precisely and fast over millions of surfaces.”

To make their technology ready for wide-scale testing, the team at imec is designing an organ-on-chip package. The chip will be embedded in a micromachined cartridge with the necessary microfluidics to bring in the solutions to allow the cells to grow and, of course, the candidate drugs that need to be tested. Eventually, this could evolve in a package with several cell cultures connected though microfluidic channels—a real human-on-chip.

Adding a Fast Microscope with a Wide View

To monitor contracting heart cells and follow the speed of conduction from one cell to the next, researchers need to observe the rapidly changing shape of a relevant number of cells. This requires a microscope with a large field of view and a high imaging speed. Up to now, scientists had to do with traditional phase-contrast microscopes, a bulky and expensive solution that cannot be scaled to a point-of-care solution.

“What we need is an on-chip microscope,” says Braeken. “The solution we have been working on is based on holographic imaging instead of glass optics—a very compact and simple setup that only requires a coherent light source, a CMOS image sensor, and a processor to do fast image reconstruction. The image capturing and interpretation is completely digital, eliminating the need for manual intervention or mechanical calibration and focusing.”

Here is how it works: The microscope’s coherent light source (e.g., a laser) shines on the sample. Then, on a digital image sensor, the interference is recorded between the light that has interacted with the object and a reference beam (the original light beam). Last, the hologram is processed to reconstruct the image and extract all the information you would need.

Dries Braeken says, “with this microscope, you can take in a whole monolayer of heart cells and follow the contraction as it sweeps through the colony. Adding chemical compounds, you can visualize and measure how the contraction is affected. In some drugs, for example, you see the coordinated contraction falling apart in an uncoordinated rustle, a panic in the cell layer. That is when your heart would stop pumping.”

Have a Patient? First Test Him on a Chip!

With stem cell technology maturing, it is now possible to grow cells with a desired generic makeup.  For example, scientists could take skin cells from someone with Parkinson’s disease and grow cells of various organs. By connecting these organs, they would arrive at a “disease-on-a-chip” that would be a model to test potential drugs against Parkinson’s disease and check if they are not toxic and have the desired effect on various cells.

“So what you’d really want is to test the patients themselves before you decide on any drug therapy,” concluded Braeken. “With iPSC technology, it is now possible to sample a patient’s skin and grow a whole array of specialized cells. And with silicon technology, we believe, it is possible to build a test lab for those cells. A lab, moreover, that can be fabricated like commodity chips—cheap, precise, and in the quantities needed for a real point-of-care test in hospitals.”

But the ultimate in in vitro testing would be the “patient-on-a-chip.” Everyone has a different genetic makeup, resulting, for example, in a subtly different metabolism that will have its effect on whether drugs are taken up, how, and the speed at which they are broken down, and what effects they have. These individual genetic profiles can result in a drug being toxic for one person and life-saving for another.

Jan Provoost ([email protected]) is a science editor at  imec.


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