Hybrid solid-liquid optics enable scalable, high-resolution light-sheet microscopy across diverse immersion media

Area of Science:

• Biomedical Imaging
• Optical Engineering
• Cell Biology

Background:

• Data-driven biological discovery requires scalable, affordable 3D imaging from subcellular to organ scales.
• Current high-resolution imaging methods (tissue clearing, expansion microscopy, light-sheet microscopy) face limitations in scalability, throughput, and accessibility due to detection optics.

Purpose of the Study:

• To overcome the limitations of current optical detection systems in biological imaging.
• To introduce a novel optical framework for enhanced resolution and scalability in 3D microscopy.

Main Methods:

• Introduction of hybrid solid-liquid optics (HySIL), a flexible refractive design framework.
• HySIL utilizes a solid optical element and a refractive index (RI)-matched liquid as a continuous optical system.
• Implementation as SCOPE and Super-SCOPE systems for aberration-corrected light-sheet microscopy (LSM) with long-working-distance air objectives.

Main Results:

• Achieved submicron-resolution, aberration-corrected LSM.
• Demonstrated high-resolution volumetric imaging in diverse biological samples: cleared/expanded mouse, salamander, cavefish brains, human iPSC-derived brain organoids, and large human tissues for 3D histopathology.
• HySIL systems offer enhanced optical performance, low cost, long working distances, and multi-immersion compatibility.

Conclusions:

• HySIL provides an accessible and scalable foundation for next-generation volumetric imaging.
• This technology enables data-driven biological discovery across various scales and sample types.
• The framework addresses fundamental limitations in optical detection for advanced microscopy.