Genoa (Italy), 15th January 2026 - Researchers at Istituto Italiano di Tecnologia (IIT-Italian Institute of Technology) have developed an innovative microscopy technique capable of improving the observation of living cells. The study, published in Optics Letters , paves the way for a more in-depth analysis of numerous biological processes without the need for contrast agents. The next step will be to enhance this technique using artificial intelligence, opening the door to a new generation of optical microscopy methods capable of combining direct imaging with innovative molecular information.
The study was conducted under the guidance of Alberto Diaspro, Research Director of the Nanoscopy Unit and Scientific Director of the Italian Nikon Imaging Center at IIT, by Nicolò Incardona (first author) and Paolo Bianchini.
Optical microscopy is an indispensable tool for studying cells, as it allows them to be observed in detail using natural light to understand fundamental biological processes. However, the transparency of cells makes them almost invisible under an optical microscope unless they are treated with contrast agents, ranging from histological staining to fluorescence labeling. To overcome this limitation, various techniques exploiting the properties of light have been developed over time to increase contrast and improve visualization. These include polarization microscopy, which highlights specific cellular components using polarized light, and dark-field microscopy, which illuminates only the edges of the sample to reveal otherwise imperceptible details. While extremely useful, these techniques often do not provide sufficient spatial visual detail for molecular analysis.
For this reason, super-resolution fluorescence optical microscopy is currently the most widely used technique for studying cells. It employs luminescent molecules that bind to specific cellular components, making them clearly visible and identifiable in four dimensions—spatial and temporal—under the microscope. One example is DAPI, which binds to the cell nucleus and emits a characteristic blue light, allowing for its immediate identification.
In this context, IIT researchers have combined polarization microscopy with dark-field microscopy, creating a new technique capable of achieving high contrast without resorting to fluorescence. In this way, the integrity of the samples is preserved, offering a more authentic view of cells.
"The idea is to use this technique to study chromatin, the complex formed by DNA and proteins located in the cell nucleus. Understanding how chromatin is organized and how it changes over time is essential for comprehending numerous biological processes and identifying the alterations underlying many diseases," says Nicolò Incardona, a researcher of the Nanoscopy Unit, who recently returned to Italy after seven years of research at the University of Valencia in Spain.
Although the new technique represents a significant step forward, it still has a limitation compared to fluorescence microscopy: it cannot specifically distinguish different cellular components. To overcome this obstacle, the Nanoscopy team is working on the development of an integrated system that combines it with fluorescence microscopy, capable of providing molecular nanoscale information. The goal will be to obtain images of the same sample using both techniques and exploit their correlation to train an artificial intelligence model to transform the former into the latter.
"Our next goal is to build an AI model capable of generating fluorescence images with molecular content, thus specific, from those obtained with our technique, thereby eliminating the need for labeling the cells under analysis," says Alberto Diaspro, coordinator of the Nanoscopy Unit. "This is an ambitious objective that could pave the way for a new generation of completely non-invasive microscopy techniques."
