4D printing makes human tissue models more realistic

Scientists are becoming increasingly good at mimicking human tissue in the lab. This helps make drug testing safer, more effective, and less dependent on animal experiments. In his PhD research at Utrecht University and UMC Utrecht, Marc Falandt developed biomaterials whose properties can be adjusted even after they have been 3D-printed, effectively adding a fourth dimension: time. He also created a hybrid material that is both mechanically robust and flexible enough to allow cells to move and grow. Together, these innovations bring the biofabrication of realistic human tissue an important step closer. Falandt will defend his PhD on Thursday 13 November.

Today, around 90 percent of experimental drugs fail in human trials, often because animal studies do not accurately predict how medicines behave in people. To address this and reduce reliance on animal testing, researchers are increasingly turning to laboratory-grown human tissues, known as in vitro models. These models typically consist of a 3D-printed biomaterial scaffold on which human cells can grow and organise themselves. Such systems are now widely used not only to test drug effects, but also in regenerative medicine.

Complex cell environment

Despite major progress in tissue engineering, creating fully functional human tissue remains a significant challenge. One of the main obstacles is the lack of biomaterials that can truly mimic the dynamic environment surrounding cells. This environment, known as the extracellular matrix (ECM), is composed of proteins and sugars that provide support, connect cells, and transmit essential biochemical signals. To recreate this in the lab, biomaterials must not only resemble the ECM but also be able to change as cells grow and mature. However, most existing materials remain static after printing.

4D printing is the only way to introduce specific functions at precise locations

Adjustments after 3D printing

In his research, Falandt developed biomaterials that provide a dynamic environment and can be adjusted even after they have been 3D-printed, a process referred to as 4D bioprinting. He designed specialized hydrogels that can be functionalized with bioactive molecules without losing their activity. Using volumetric bioprinting, a technique that uses light to create an entire 3D structure in a single step rather than layer by layer, he first produced the scaffold.

He then added bioactive molecules using photografting, a technique that also relies on light, this time to attach molecules only to the illuminated areas of the material. One of the molecules he used was a growth factor that stimulates the formation of blood vessels. In regions where this growth factor was incorporated, cells showed increased movement and penetrated the material more effectively than in untreated areas.

“4D bioprinting is crucial,” says Falandt. “It’s the only way to introduce specific functions at precise locations. Until now, adding a growth factor typically resulted in either uncontrolled proliferation everywhere or no effect at all.”

Soft materials are hard to keep in a defined shape, yet shape is crucial for function

Widely applicable

To ensure the technique can be used across many different biomaterials, Falandt developed a supplement called AddGraft. When mixed into a biomaterial, AddGraft enables biological functions to be introduced later through 4D photografting. He also designed a temperature-responsive method to improve printing resolution. The process starts by creating relatively large channels that can easily be filled with cells; when the material is subsequently warmed, it shrinks to its natural scale, yielding fine, tissue-like structures.

Hybrid hydrogels

Finally, Falandt developed an innovative biomaterial that mimics the natural dynamics of the extracellular matrix. This new material, called Hybrigel, combines mechanical strength with enough flexibility to let cells move and reorganize. He achieved this by using reversible molecular bonds that can break and reform in response to conditions such as temperature. As a result, the hydrogel offers a stable structure while remaining dynamic, allowing cells to migrate without the material collapsing.

“Soft materials are hard to keep in a defined shape, yet shape is crucial for function,” Falandt explains. “At the same time, many cells cannot survive in a rigid environment. This new hydrogel resolves that tension.”