Breaking the Size Barrier: Sub-Micron 3D Imaging with ClearScope

In whole-brain microscopy, researchers have long faced an unforgiving trade-off: image at the resolution needed to resolve individual neurons, or image specimens large enough to capture intact organs — but not both. Traditional light-sheet microscopes typically use an orthogonal arrangement of illumination and detection optics that constrains specimen lateral dimensions to roughly 10–15 mm.

Anything larger — such as intact primate specimens or human brain tissue sections — usually requires physical sectioning, which destroys the very connectivity researchers are trying to study.

Our latest publication in the Journal of Imaging, co-authored by the team here at Arnas Technologies, introduces ClearScope — a fully integrated Light-Sheet Theta Microscope (LSTM) specifically engineered to eliminate this limitation.

Rather than conventional orthogonal geometry, ClearScope employs two oblique illumination paths oriented at 64° to a perpendicular detection axis. This theta geometry ensures that the illumination and detection optics never physically collide, regardless of the specimen's lateral size.

The system operates by scanning a thin excitation line across the field of view, synchronized with a rolling-shutter camera readout. The result is a compact, single-box instrument that achieves:

• Sub-micron lateral resolution: 0.34–0.37 µm FWHM with a 10× objective
• Unconstrained lateral size: Effectively unlimited lateral specimen extent
• Significant imaging depth: Up to 17 mm with a 4× objective

ClearScope was designed for reproducibility and high-performance laboratory environments:

Uniform Precision: PSF measurements show lateral FWHM values are uniform from the center to the corners of the field of view.

Intelligent Refractive Index Compensation (IRIC): The system automatically adjusts light-sheet position and focus as a function of tissue depth. This allows compatibility with various clearing protocols — from water-based (RI 1.33) to iDISCO (RI 1.56) — without changing immersion media.

Turnkey Integration: A detection objective changer enables switching between 4× and 20× magnification during a single session with better than 3 µm repeatability.

Minimal Photobleaching: Dual light sheets keep optical power at the specimen between 1–15 mW, resulting in no measurable signal degradation during acquisition.

The paper demonstrates ClearScope's power across several biologically relevant use cases:

• Whole Mouse Brain: Imaged an entire intact brain in 8 hours and 32 minutes using a 4× objective in a fully unattended "lights-out" operation
• Subcellular Detail: At 20× magnification, individual dendritic spines and human hippocampal CA1 pyramidal neurons were resolved with sufficient quality for automated 3D reconstruction
• Anatomical Mapping: Whole-brain datasets were registered to the Allen Mouse Brain Common Coordinate Framework (CCFv3) for informed analysis of vascular networks and neuronal processes

At Arnas Technologies, we specialize in building the intelligent scientific workflows required to handle the terabyte-scale data generated by systems like ClearScope. High-resolution 3D imaging is the foundation; the real value lies in the analysis, deconvolution, and quantification that turn raw data into publishable insights.

Read the full open-access article

Fay MG, Lang PJ, Denu DS, O'Connor NJ, et al. J. Imaging 2026, 12(3), 118.