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Surrounding every cell is a network of proteins and other substances. This network is called the extracellular matrix, literally the material outside the cell. It does more than hold cells in place. It also passes on signals that determine how cells grow, move, and function. At the same time, cells constantly remodel this network: building it up, breaking it down, and reshaping it.

That makes it very hard to recreate in the lab. Yet that is exactly what researchers are trying to do, because good artificial materials are essential for medical research.

Building blocks that organize themselves

Veenbrink worked with materials built from small molecules called ureido-pyrimidinone, or UPy for short. What makes UPy molecules special is that they can connect to each other on their own, forming larger structures without being forced to do so. They are also highly adaptable: small changes to the molecule can alter the properties of the entire material.

A central idea in this research was that cells don't just respond to what is in a material. They also respond to how those substances are presented to them.

Artificial material for mini kidneys

The first part of the research focused on mini kidney tissues, also known as tubuloids. Tubuloids are small tissue structures grown in the lab that closely resemble real kidney tubules. They are used to study kidney disease and test medicines.

Normally, tubuloids are grown in a material derived from animals. That material has a drawback: its composition varies from batch to batch, making it hard to compare experiments.

Veenbrink tested UPy materials as an alternative. One version, a UPy molecule linked to a small piece of the structural protein laminin, gave the best results. The tubuloids grown in it had the most normal shape and the correct hollow structures on the inside. Another version, linked to a piece of the protein fibronectin, more often produced irregular shapes. This showed that cell behavior depends strongly on which signals are present and how they are displayed.

Bacteria-killing materials

In the second part of the study, Veenbrink looked at UPy materials containing bacteria-killing substances called antimicrobial peptides. These are small molecules that can destroy bacteria. The idea is to build such substances into materials so that those materials can help prevent infections.

Some combinations were still effective against different types of bacteria. But the results depended heavily on both the peptide used and the material it was placed in. In some combinations, the bacteria-killing effect held up well. In others, it became weaker.

The conclusion: you can't predict how well such a material will work based on the peptide alone. The surrounding material plays an equally important role.

Faster testing with cell photography

To evaluate more materials more quickly, Veenbrink also applied a specialized microscopy method called Cell Painting. In this method, different parts of cells are labeled with dyes. Microscope images are then taken, and hundreds of features such as cell shape and appearance are measured automatically.

The method worked well for certain biological signals, particularly growth factors, which are substances that stimulate cell growth. But not for all materials: some interfered with the dyes or made imaging difficult, which means Cell Painting can't be used across the board.

Even so, it is a valuable step forward. With Cell Painting, researchers can test far more materials in far less time than with traditional methods.

Small differences, big impact?

Finally, Veenbrink looked at small chemical differences between batches of one important UPy building block. Those small differences did affect how the molecules clustered together and what structures they formed. But under the conditions tested, they did not lead to clearly different cell responses.

This suggests that the material is sensitive to small chemical variations, but that the effects on cells can still remain stable.

The ingredients and the assembly both count

Veenbrink's research shows that creating good artificial cell materials requires more than just choosing the right building blocks. It is also about how those building blocks come together and how you accurately measure their effects on cells.

By better aligning those three elements, namely ingredients, structure, and measurement, this field can move away from trial and error. That will make it possible to design materials more deliberately, understand them more deeply, and improve them more quickly.

This research was conducted within ICMS (Institute for Complex Molecular Systems) at Eindhoven University of Technology and was funded by the National Growth Fund Big Chemistry (1420578), SUPRALIFE (101079482), and DARTBAC (NWA.1292.19.354).