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Organ donors can save lives, for example, those of patients with kidney failure. Unfortunately, there are too few donors, and the waiting lists are long. 3D bioprinting of (parts of) organs may offer a solution to this shortage in the future. But printing living tissues, bioprinting, is extremely complex and challenging.

The team of Riccardo Levato at UMC Utrecht and Utrecht University is now taking an important step toward printing implantable tissues. Using computer vision, a branch of artificial intelligence (AI), they've developed a 3D printer that doesn't just print, it also sees and even co-designs.

Their research was today in Nature. With this innovation, they tackle one of the biggest challenges in 3D bioprinting: improving both the survival and functionality of cells in printed living tissue. But how exactly does that work?

We usually associate 3D printing with building structures layer by layer. But there are other forms, such as volumetric bioprinting. This technique creates a complete structure in a single step, using a light-sensitive gel that solidifies when exposed to cell-friendly laser light. The advantage? It is incredibly fast, taking just seconds, and much gentler on living cells.

To produce a high-quality print, it is crucial to understand what's inside the printing material, so that the printed object is built as optimally as possible. The new technology, called GRACE, makes that possible. It opens up new possibilities for bioprinting functional tissues, and brings us closer to repairing tissues, testing new drugs, and even replacing entire organs.

What is 3D-bioprinting?

In 3D bioprinting, researchers use living cells to create functional tissues and organs. Instead of printing with plastic, they print with living cells. This comes with great challenges. Cells are fragile and wouldn't survive a regular 3D printing process. That's why Levato's team developed a special bio-ink, a mix of living cells and nourishing gels that protect the cells during the printing process.

With the advancements in bio-inks, layer-by-layer 3D bioprinting became possible. But this method is still time-consuming and puts a lot of stress on the cells. Researchers from Utrecht came up with a solution: volumetric bioprinting.

Volumetric bioprinting is faster and gentler on cells. Using cell-friendly laser light, a 3D structure is created all at once. "To build a structure, we project a series of light patterns into a spinning tube filled with light-sensitive gel and cells," Levato explains. "Where the light beams converge, the material solidifies. This creates a full 3D object in one go, without having to touch the cells." To do this, it is crucial to know exactly where the cells are in the gel. GRACE now makes that possible.

Sammy Florczak, a Ph.D. student in Riccardo's lab, worked on the development of GRACE, short for Generative, Adaptive, Context-Aware 3D printing. He built a new device in a specialized lab, using advanced laser technologies. Before entering, a red light signaling "LASER" shows whether it's safe to go in.

Laser light plays a crucial role, not just in the printing step, but also in the added imaging step that sets this new technology apart. GRACE combines volumetric bioprinting with this advanced laser-based light-sheet imaging. But what can we do with that?

Smart blood vessels around living cells

One of the biggest challenges in 3D bioprinting is creating functional blood vessels. Blood vessels are essential to provide oxygen and nutrients to the cells, and thus printing these blood vessels in the correct place is key to creating viable tissues.

Yet, in conventional printing methods, a 3D design is made before knowing where the cells are located in the light sensitive gel and thus where the blood vessels must be printed. With GRACE, the printer "sees" where the cells are located and, within seconds, designs a network of blood vessels around those cells as effectively as possible.

"In the past, printing always depended on the designer's blueprint. Now, GRACE contributes to the design itself," Florczak explains. "The printer 'sees' what kind of cells are in the material, and where they are. Then, using AI tools, it creates a matching design for the object to be printed. This new printer essentially has its own 'eyes' (the laser-based imaging) and 'brain' (the new AI software). That level of customization leads to tissues that survive and function better."

GRACE can do more than create adaptive blood vessel networks. The technology can also align multiple printing steps automatically. Take a piece of printed bone tissue, for example, that later needs a layer of cartilage added. Normally, that is a complex process with a lot of manual work. GRACE scans the existing tissue and automatically designs and prints a second layer that fits perfectly on top. All at the high printing speed of volumetric bioprinting, creating cm³-sized objects within seconds.

Another challenge in bioprinting is that light can sometimes be blocked, for example by previously printed parts of the structure. This can create shadows and flaws in the final product. GRACE can solve this too. By scanning the surface of any obstacles, the system automatically adjusts the light projection. This makes the print more precise and consistent. Moreover, this allows pre-made objects to be inserted into the printing vial. Think, for example, of a stent in which you could print blood vessel cells or objects that can release medicines.

Just the beginning

Bioprinting is highly promising, but significant work is still needed to translate this technology to the clinic. Riccardo underlines that further research is needed to determine how printed cells can mature to replicate the functionality of native tissues. Even considering the challenges ahead, Riccardo is not afraid to dream big.

"This first work on GRACE is just the beginning. We are now working on increasing the amount of cells that can be printed, so that other tissues like heart and liver can also be printed. Moreover, we would like to make this technique openly accessible to other labs, so other could apply it to their printing method."