Difficult contact arrangement
Actually, they live in separate worlds: neurons and computers. But both of them work electrically. Reason enough for Freiburg scientists to establish contact between the two. But how do you ensure that they find each other attractive over the long term?
The approximately 220 different cell types that make up our body are by no means lone fighters – they only make human life possible when they combine to form tissues and ultimately organs. It is precisely this "social behavior" that is of great importance in the research and therapy of many clinical pictures. Example of Alzheimer's dementia: How is the transmission of signals from nerve cell to nerve cell disturbed? What influence does a new active ingredient have? For such questions, researchers are still dependent on examining samples from living tissue. But with so-called cell chips, such clinical analyzes could be simplified and animal experiments minimized.
Depending on the area of application, different cell types are to be attached to chips, similar to those that play a role in computer technology. There they grow and make contact with the smallest electronic components, with the help of which they can then be manipulated and their behavior controlled.
The University of Freiburg, more precisely at the Institute for Microsystems Technology, is also interested in the cell chips. The scientists around Jürgen Rühe from the Chair of Chemistry and Physics of Interfaces are primarily concerned with the surfaces of the chips on which cells are to grow - because the "chemistry at the interface" determines where the cells prefer to settle on the substrate. Photolithographic processes from microsystems technology can be used to create high-precision miniaturized structures on wafer-thin wafers made of silicon, glass or plastic, exactly the right size for individual cells."We then adjust the chemistry of the surface in such a way that certain areas are attractive for cell adhesion, while cell attachment to other areas does not occur," explains his colleague Markus Biesalski.
Tricking with proteins
In the natural environment of the cells, proteins provide the vital connection to the outside world. Specialized proteins embedded in the cell membrane make contact with proteins of the connective tissue or neighboring cells and lead to an organized structure of tissue. This not only provides the necessary structural cohesion, but also enables signals to be transmitted internally. Many vital processes, from cell division to cell growth, are influenced in this way.
The Freiburg scientists want to replicate the natural process with two different strategies. "The chemical attachment of signaling molecules, such as fibronectin, to the artificial carrier material of the chip is a possible way of increasing the attractiveness of the surface for cells," explains Biesalski. Biomimetics is the name of this strategy, which tries to imitate natural phenomena with synthetic materials, in this case tricking the cells into thinking they are in their natural environment. If you dip a chip equipped with the appropriate proteins into a cell solution, the cells independently look for anchor points on the surface.
However, fibronectin is difficult to handle in the laboratory. In the next step, the researchers therefore use their knowledge of the structure of this protein. "We know from structural biology that there are active binding sequences in fibronectin. This means that not the entire protein binds to the receptor on the surface of the cell, but only a very small part - so-called peptide ligands," explains the chemist. Instead of the complex entire protein, the researchers chemically attach only the short, active section, for example the tripeptide "RGD", which is only a few amino acids long, to the chip."With this promising approach, we are attempting to gain a fundamental understanding of both how cells react to this surface chemistry and how to easily influence the behavior of cells on surfaces," says Biesalski.
In the second strategy, too, proteins play the role of attracting contact mediators - in this case, however, they come from the cell itself. "We know from experience that some surfaces are generally attractive to cells," says Anke Wörz, a doctoral student at the institute for microsystems technology. Cells then form their own adhesion-promoting molecules there and attach themselves to the material on their own. By combining them with surfaces that have a cell-repellent effect, the allocation of the cells to certain areas of the chip can be controlled, depending on the desired end result.
Printed Matter Cell
The researchers achieve an even more precise distribution of the cells, which also allows several cell types to be applied at the same time, using a technology that is familiar from everyday use: instead of ink, dot matrix or inkjet printers print a nutrient solution enriched with one or more cell types, on the chip."The metering of today's inkjet printers is so precise that we could theoretically even print individual cells," explains Wörz. However, no matter how precise the positioning of the individual cells by the print head, the surface chemistry of the chips remains important. This is because cells can migrate to a spot on the disc that is attractive to them or even – if the environment is too uncomfortable – detach themselves from the interface again.
All strategies have the same goal: to subdivide a surface into attractive and repulsive areas with as much submicrometer precision as possible. Once the position of a specific cell and its neighbors has been predetermined, tissue can be built up in a targeted manner. "So far, this has worked very well with connective tissue cells. Unfortunately, neurons are a bit more difficult to control," explains Anke Wörz.
Growing Webs and Webs
If it were possible to connect the nerve cells on the chip surface to form networks, they could be stimulated with a transistor buried under the surface and the reaction measured a few cells further away – also with a buried transistor. "It is only a matter of time before cell chips can be used in clinical practice"
(Markus Biesalski) In the future, it would be possible to conveniently test pharmaceuticals with cell chips "in vitro" and the lives of some laboratory animals would be spared. The Freiburg scientists also see possible future applications in the field of tissue engineering.
In both cases, the innovative technology promises to simplify both clinical analyzes and the targeted cultivation of cells. "However, further basic research is necessary before it can be used in practice," summarizes Dr. Biesalski. "However, it is only a matter of time before cell chips can be used in everyday clinical practice."
