You may have heard about people making paintings on a grain of rice, but is it possible to create something inside a living cell, which is thousands of times smaller? Well, for the first time, a team of researchers has achieved this nearly impossible feat. 

They 3D-printed microscopic bar codes and an elephant inside living cells, and that too without causing any changes in their DNA. This technique could kickstart a whole new way of studying, labeling, and customizing cells without altering their genetic material. 

For instance, “one of the applications we explored is barcoding, which involves writing a specific code on each cell for the purpose of identification and long-term tracking of the cell,” the study authors note.

Moreover, this unique 3D printing approach could also enable scientists to build sensors inside cells and track them with tiny lasers. These tools could transform how we monitor and study cellular behavior in real time. 

But the main question is how do you actually 3D print something inside a living, fragile cell without killing it?

The science of sketching an elephant inside a cell

3D printing has come a long way. People now create everything from robots to homes and even rocket engines. However, 3D printing inside something as small as a cell has remained out of reach. Cells are so delicate that even the slightest disturbance can damage or kill them. 

To print microscopic structures, scientists need to inject a liquid material called a photoresist into the cell. This special material solidifies when exposed to focused laser light, making it essential for creating tiny 3D shapes. However, most photoresists are toxic to cells, and the injection process itself can rupture the cell membrane. 

These hurdles have made intracellular 3D printing nearly impossible—until now. To break through this barrier, the researchers used a clever approach called two-photon polymerization (TPP). This process begins with injecting a droplet of a liquid polymer, the photoresist, into the cell’s cytoplasm. 

This photoresist solidifies only when it absorbs two laser photons at the same time, a process that requires extremely precise focusing of light. A powerful, highly focused laser beam is then used to draw tiny structures inside the cell. The photoresist solidifies only at the laser’s focal point, which lets the researchers build detailed 3D structures layer by layer, without damaging the rest of the cell. 

Once the printing is done, any leftover photoresist is dissolved away, leaving only the tiny printed object inside the cell. To further improve cell survival, the researchers picked a biocompatible photoresist, one that’s less toxic than standard versions, but even then, injecting liquid into cells is inherently risky. 

This is why, many cells died from membrane damage or the effects of the polymer. However, around half of the cells made it through, and in some cases, the results were astonishing. The researchers managed to print a 10-micrometer-long elephant, along with barcode-like patterns and tiny spherical microlasers on these cells.

A few cells continued to function normally, even dividing and passing the 3D-printed structure to one of their daughter cells. Moreover, some of theprinted structures, like the microlasers, once lit, emit a unique color of light based on their size, providing a potential tool to give every cell its own light signature for tracking.

“Tagging and tracking of cells has been reported with micro-particles of different shapes acting as either graphical or spectral barcodes (microlasers),” the study authors note. This work “lays the groundwork for a new class of intracellular bioengineering tools and applications,” they further added.

A new way to customize living cells

The study authors suggest that the tiny elephant inside the cell is just the beginning. This breakthrough opens up an entirely new dimension in biology, i.e., reprogramming cells from the inside, without changing their DNA. 

For example, apart from light-emitting tags, scientists could use this technique to print custom tools directly inside living cells, like mechanical levers to measure force, barriers to isolate parts of a cell.

It’s also a potential game-changer for studying how cells function, tracking disease progression, or designing smart cells with new abilities. However, the technique is not yet perfect. Many cells still die after the injection, and the size of printed structures is limited by the volume of the injected droplet. 

To overcome this, the team suggests using a water-soluble, hydrogel-based photoresist in the future that can spread throughout the cell, enabling larger or more complex structures to be printed anywhere inside. Hopefully, further research will achieve this feat and make the process more practical and scalable.

The study is available on arXiv.