Many hopes rested on so-called tissue engineering: With the help of stem cells, skin and other organs could be grown, thereby enabling better wound healing and better transplants. Although some of this is already a reality, the level expected around 20 years ago has not yet been achieved because the stem cells do not always bind to the required host material as they should in theory. An international research team led by chemist Professor Shikha Dhiman from Johannes Gutenberg University Mainz (JGU) has now found the reason for this: "Whether an interaction between model cell membrane and matrix material occurs depends not only on the strength of the interaction but also on the speed at which the binding partner molecules move. The understanding of this interaction that we have now gained is crucial for the development of effective biomaterials," says Dhiman. The team's results were recently published in the renowned scientific journal PNAS.

To artificially grow biological tissue in the laboratory, biotechnologists typically place stem cells onto matrix materials, usually gels. These gels dictate how the cells should behave and develop. For this to succeed, however, the cells must bind to the matrix materials. For a long time, it was assumed that it would be sufficient to add molecules to the gel that bind strongly enough to the receptors in the cells – these molecules are called ligands. But this turned out to be a fallacy. In theory, this should work, but in practice it often doesn't. While most researchers start by optimizing the matrix material to solve this problem, Dhiman, among others, with Professor Bert Meijer from the Eindhoven University of Technology, has now investigated the first point of interaction: the bond between single fibers of matrix and model cell membrane. "Until now, the strength of the interaction between ligands and receptors has always been considered. But we discovered that whether a model cell membrane can bind to the fiber depends primarily on the speed at which the binding partner molecules move in the model cell membrane or in the fiber," says Dhiman. If the speed of the ligands in the fiber and of the receptors in the model cell membrane are similar, they can find each other and couple. "Even the weakest bond can lead to interaction between the molecules if their speeds are similar," says Dhiman. "However, if one of the binding partners moves quickly and the other slowly or not at all, cells will not bind to the gel. Although this is basic research, it now provides a clearer picture of how these interactions work at the molecular level."

At similar speeds, the binding partners gather

For their studies, the researchers used super-resolution microscopy, which allows them to image individual receptors and ligands. How do the individual molecules behave? To answer this question and track the movements of the molecules under the microscope, Dhiman and his colleagues worked with single fibers instead of bulk gel. "This reduction to single fibers was important to clearly understand the interactions," Dhiman explains. "If the molecules in the model cell membrane and in the fiber move with similar speed, they tend to group together. The binding partners therefore gather on both sides at the contact point between the fiber and the model cell membrane – instead of individual compounds, it is then usually an entire group of receptors and ligands that ensure the binding. Even low binding strengths are then sufficient," says Dhiman.

The results could be groundbreaking for tissue engineering, but also for other medical applications such as immunotherapies or drug delivery. Drug delivery involves delivering the active ingredient directly to the site of action to maximize therapeutic effect and minimize side effects. "In the long term, this knowledge could lead to breakthroughs in tissue repair and regenerative medicine, as well as advanced medical implants that work in harmony with the body's cells," says Dhiman.