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Breakthrough in distortion-free tissue transparency reveals neurons in 3D

Caption: A new method for making tissues see-through without changing their structure is making it possible to image the details of neurons in 3D. Credit: Tsinghua University

A new technique makes tissue samples see-through without deforming them — offering unprecedented insights into neurons in their natural state.

Microscopes have long been the biologist’s window into the body’s inner workings. But preparing tissue for imaging — whether by slicing it thinly or using chemicals to make it transparent — often deforms delicate structures and limits the accuracy of observations. Now, a new method offers clarity without compromise.

Researchers at Tsinghua University have developed a method for making biological tissue transparent without the usual side effects. Unlike traditional techniques that can shrink or swell samples, this approach maintains their original structure. Published recently in Cell, the new technique enables high-resolution, 3D imaging of entire organs with remarkable clarity1.

“It could significantly advance our understanding of biological systems, particularly delicate structures in the brain,” explains Kexin Yuan, an associate professor at the School of Biomedical Engineering at Tsinghua and co-author of the study. He adds that the technique could potentially revolutionize drug discovery by helping to visualized a drug’s mechanisms in situ, as well as improve the diagnosis of diseases by allowing clinicians to examine pathological tissues in greater detail.

A new path to transparency

Traditional tissue-clearing techniques — which render biological samples transparent for imaging — typically rely on organic solvents or aqueous solutions. These agents deform tissues through swelling or shrinkage and often interfere with fluorescence, the glow emitted by dyed or engineered cells that makes structures visible.

A new method, known as VIVIT (vitreous ionic-liquid-solvent-based volumetric inspection of trans-scale biostructure), overcomes these challenges. It relies on a specialized ionic liquid (APIL) that preserves structural integrity during tissue clearing.

APIL is an ionic liquid that supports a rapid cooling process known as vitrification, which solidifies liquid into a glass-like state. When tissue samples are immersed in APIL under near-freezing conditions, the solution induces this state without forming ice crystals. This prevents the structural damage typically caused by freezing and preserves tissues in a finely organized, clear condition suitable for high-resolution imaging.

APIL’s refractive index also reduces light scattering, enabling deep light penetration that aids visibility. And its compatibility with water-based samples eliminates the need for dehydration, a common step in some other clearing methods.

In addition, the researchers discovered that VIVIT enhances the fluorescence intensity of the dyes and proteins used for cell labeling, an effect not observed with conventional clearing agents. “We were very surprised to discover this,” Yuan says.

Caption: A new distortion-free method for making tissues see-through for imaging is already leading to insights into how neurons process visual and auditory information. Credit: Tsinghua University

Mapping the brain in 3D

To demonstrate VIVIT’s capabilities, the team applied the method to mouse brain tissue. Using light-sheet microscopy, they captured images of an entire brain made optically transparent.

Genetically modified neurons emit a yellow fluorescent glow, revealing a delicate network of axons — slender projections that transmit signals between neurons.

For higher-resolution imaging, the researchers then sliced the brain into thinner sections and imaged them using spinning disk and super-resolution confocal microscopy. These slices were digitally reconstructed into a 3D model based on earlier scans, enabling the team to trace individual neurons from input to output regions.

Their analysis showed that distinct types of neurons in the thalamus specialize in different senses — some processing auditory signals, others visual — and relay them to separate brain areas.

“It’s the first time a neuron’s full trajectory has been mapped in 3D, from synaptic input to axonal output,” Yuan says.

A new 3D imaging era

The researchers also applied VIVIT to human brain tissue samples, uncovering more details about inhibitory control mechanisms that prevent neurons from firing excessively a process implicated in conditions such as epilepsy.

Yuan explains that the technique’s ability to preserve tissue integrity while enabling deep, multiscale imaging could revolutionize fields ranging from spatial transcriptomics and proteomics, which allow scientists to study how cells and other components interact, to clinical diagnostics. It could also deeply change therapeutic development, by helping to identify new therapeutic targets and evaluate pre-clinical drug efficiency. “It may help these disciplines finally step into a truly three-dimensional era,” he says.

Yuan’s team plans to integrate artificial intelligence with VIVIT to automate image analysis and enhance diagnostic potential. Such advances may ultimately extend VIVIT’s impact from neuroscience research to advances that help doctors analyze tissue samples and medical images to detect and monitor disease, and supports precision and personalized medicine.

“Once we combine our method with AI, we could do a lot,” he says.

Caption: Kexin Yuan, an associate professor at Tsinghua University, advances biomedical imaging and tissue-clearing techniques for neuroscience research. Credit: Tsinghua University

Reference

Gao, Y., Xin, F., Wang, T., Shao, C., Hu, Y. et al. VIVIT: Resolving trans-scale volumetric biological architectures via ionic glassy tissue Cell (2025).\

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Breakthrough in distortion-free tissue transparency reveals neurons in 3D

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Breakthrough in distortion-free tissue transparency reveals neurons in 3D

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