Lensless On-Chip Microscopy

Shaowei Jiang and Guoan Zheng developed a lensless on-chip microscopy platform. (Source: S. Flynn, U. Conn.)

When you look through a microscope, whatever is on the stage is magnified to a degree the naked eye can hardly imagine. While tradi­tional micro­scopy techniques allow miniscule details to come into view, standard equipment doesn’t provide us with the full picture. Most optical micro­scopes have a limited field of view, only one to two millimeters. This is a major incon­venience for life scientists and patho­logists who rely on microscopy to analyze and diagnose disease, since prepared tissue samples have dimension in the centi­meter range.

To address this unmet clinical need, a new microscopy platform developed at University of Connecticut removes a central component of tradi­tional micro­scopes – objective lenses. By going lensless, researchers can actually provide clinicians a fuller picture, leading to more accurate diagnoses. Guoan Zheng, a University of Connec­ticut professor of biomedical engi­neering, recently reported about his findings on a successful demons­tration of a lensless on-chip micro­scopy platform . This platform eli­minates several of the most common problems with conven­tional optical micro­scopy and provides a low-cost option for the diagnosis of disease.

Rather than using lenses to magnify the tissue sample, Zheng’s platform relies on a diffuser that goes between the specimen and the image sensor or camera. The diffuser randomly moves to different positions while the sensor acquires the images, gathering the encoded object information that will later be used to recover an image for viewing by clinicians or researchers. At the heart of the object recovery process is the imaging technique ptycho­graphy. Ptycho­graphic imaging typically uses a focused beam to illuminate a sample and record the pattern created by the diffracted light. To recover an entire complex image – like a tissue sample – for viewing, ptycho­graphy requires thousands of patterns to be recorded while scanning the sample to different positions.

“Although ptychography has been of increasing interest to scientists around the world, broad imple­mentation of the method has been hampered by its slow speed and the requirement of precise mechanical scanning,” says Shaowei Jiang, a UConn graduate student. Zheng’s new ptycho­graphic technology addresses these issues by bringing the sample close to the image sensor. This new confi­guration allows the team to have the entire image sensor area as the imaging field of view. In addition, it no longer requires the precise mechanical scanning needed for traditional ptycho­graphy. This is because the new confi­guration has the highest Fresnel number ever tested for ptycho­graphy, approxi­mately 50,000.

The Fresnel number charac­terizes how a light wave travels over a distance after passing through an opening, such as a pinhole. The ultra-high Fresnel number used in Zheng’s experiments indicates that there is very little light diffrac­tion from the object plane to the sensor plane. Low levels of diffrac­tion mean that the motion of the diffuser can be directly tracked from the captured raw images, eli­minating the need for a precise motion stage, which is critical for conven­tional ptycho­graphy. “This approach cuts down on processing time, cost, and allows for a more complete image to be produced of the sample,” says Zheng.

With conventional lensed micro­scopy, scientists can only view a small portion of a slide during each viewing. Zheng’s platform offers a major improvement by effectively expanding the microscope’s field of view. Zheng’s current proto­type offers a 30 mm2 field of view, compared to the standard ~2 mm2. By using a full-frame image sensor in a regular photo­graphy camera, Zheng’s tech­nology allows physicians to analyze two entire slides at once. “Imagine being able to read a whole book at once instead of just a page at a time. That’s essentially what we hope our tech­nology will allow clinicians to do,” says Zheng.

Adding to its already long list of improve­ments, Zheng’s platform eliminates the need for cell staining. Normally, scientists stain parts of cells, like the nucleus, to identify how many there are. Zheng tested this platform’s ability to perform automatic cell segmen­tation using the recovered label-free phase maps. Due to its compact confi­guration and robust performance, Zheng and his team envision that their platform would be a good fit for use in a range of point-of-care, global health, and telemedicine applications. Their tech­nology can also be useful for X-ray and electron micro­scopy.

“By using our lensless, turnkey imaging system, we can bypass the physical limi­tations of optics and acquire high-reso­lution quanti­tative infor­­mation for on-chip microscopy. We’re excited to continue to refine this tech­nology for commercial and clinical appli­cations to have a tangible impact for patients and researchers,” Zheng says. (Source: UConn)

Reference: S. Jiang et al.: Wide-field, high-resolution lensless on-chip microscopy via near-field blind ptychographic modulation, Lab Chip, online 11 February 2020; DOI: 10.1039/C9LC01027K

Link: Dept. of Biomedical Engineering, University of Connecticut, Storrs, USA

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