New Microscope Lens System Delivers High Resolution at Low Cost

A team led by Raju Tomer from Columbia University has developed a new optical design for microscopes that could extend 3D tissue imaging beyond current capabilities while substantially reducing cost and complexity. The work was published in Nature Biotechnology.

High-resolution, 3D images of intact tissues—brains, cancer biopsies, and other samples—are increasingly central to modern biology and medicine. They allow researchers to map neural circuits, characterize disease, and train AI models for diagnosis. But progress has been bottlenecked by the lenses used to capture light from samples.

The tradeoffs have been persistent: oil-immersion lenses produce sharp images but are expensive, penetrate only a few millimeters, and require specific sample preparations. Less expensive air lenses can reach several centimeters into a sample but produce blurred images when used with the chemicals that make tissues transparent for 3D viewing.

The team's solution is called HySIL (Hybrid Solid–Liquid Optics). It pairs a simple, curved solid lens with a precisely matched immersion liquid so the two function as a single continuous optical system. The design allows inexpensive air lenses to deliver high-resolution images across centimeter-scale tissues and across virtually any common sample-preparation method, without hardware changes.

“We’ve broken a long-standing trade-off in microscopy between performance and accessibility,” Tomer said. “By making the immersion liquid an active optical component rather than a passive filler, we get the resolution of the most expensive lab systems with the cost and footprint of equipment that fits anywhere, from teaching labs to clinics in low-resource settings.” 

To demonstrate the framework, the team built a modular add-on device called SCOPE for existing light-sheet microscopes, along with a higher-resolution variant called Super-SCOPE. Both were also integrated with a compact, projector-based light-sheet microscope (pLSM) Tomer’s group developed in 2024, now available commercially as SLICE.

Working with collaborators across the life sciences, the team used pLSM-SCOPE to image whole mouse, salamander, and cavefish brains; lab-grown miniature human brain tissues; and intact human cancer biopsies. Because HySIL is a general framework, it can be attached to confocal, two-photon, and other imaging systems.

“A new optical concept only changes a field if labs without specialized optics expertise can actually use it day to day," said co-author Jack Glaser. “What HySIL gives us is the rare combination of lower cost and higher performance in the same instrument.”

For decades, tissue analysis has relied on thin, two-dimensional slices on glass slides. Three-dimensional imaging reveals structural features that cross-sections miss. “Tools like pLSM-SCOPE that make this kind of imaging affordable and accessible will become increasingly important as AI helps us analyze ever-larger amounts of tissue data for diagnosis and prognosis,” said co-author Hanina Hibshoosh.