Hybrid Microscope for Digital Biopsy

This side-by-side comparison of a breast tissue biopsy demonstrates some of the infrared-optical hybrid microscope’s capabilities. On the left, a tissue sample dyed by traditional methods. Center, a computed stain created from infrared-optical hybrid imaging. Right, tissue types identified with infrared data. The pink in this image signifies malignant cancer. (Source: R. Bhargava)

By adding infrared capa­bility to the ubiquitous, standard optical micro­scope, researchers at the University of Illinois at Urbana-Champaign hope to bring cancer diagnosis into the digital era. Pairing infrared measure­ments with high-resolution optical images and machine learning algorithms, the researchers created digital biopsies that closely correlated with tradi­tional pathology techniques and also outperformed state-of-the-art infrared micro­scopes.

“The advantage is that no stains are required, and both the organization of cells and their chemistry can be measured. Measuring the chemistry of tumor cells and their micro­environment can lead to better cancer diagnoses and better under­standing of the disease,” Rohit Bhargava, a professor of bio­engineering and the director of the Cancer Center at Illinois, said. The gold standard of tissue pathology is to add dyes or stains so that patho­logists can see the shapes and patterns of the cells under a micro­scope. However, it can be difficult to distin­guish cancer from healthy tissue or to pinpoint the boundaries of a tumor, and in many cases diagnosis is subjective.

“For more than a century, we have relied on adding dyes to human tissue biopsies to diagnose tumors. However, the shape and color induced by the dye provide very limited infor­mation about the underlying molecular changes that drive cancer,” Bhargava said. Tech­nologies like infrared micro­scopy can measure the molecular composition of tissue, providing quanti­tative measures that can distin­guish cell types. Unfortunately, infrared micro­scopes are expensive and the samples require special pre­paration and handling, making them impractical for the vast majority of clinical and research settings.

Bhargava’s group developed its hybrid micro­scope by adding an infrared laser and an inter­ference objective to an optical camera. The infrared-optical hybrid measures both infrared data and a high-reso­lution optical image with a light micro­scope – the kind ubiquitous in clinics and labs. “We built the hybrid microscope from off-the-shelf components. This is important because it allows others to easily build their own micro­scope or upgrade an existing micro­scope,” said Martin Schnell, a post­doctoral fellow in Bhargava’s group.

Combining the two techniques harnesses the strengths of both, the researchers said. It has the high resolution, large field-of-view and accessi­bility of an optical microscope. Further­more, infrared data can be analyzed compu­tationally, without adding any dyes or stains that can damage tissues. Software can recreate different stains or even overlap them to create a more complete, all-digital picture of what’s in the tissue. The researchers verified their microscope by imaging breast tissue samples, both healthy and cancerous, and comparing the results of the hybrid micro­scope’s computed dyes with those from the traditional staining technique. The digital biopsy closely correlated with the tradi­tional one.

Furthermore, the researchers found that their infrared-optical hybrid outperformed state-of-the-art in infrared micro­scopes in several ways: It has 10 times larger coverage, greater consistency and four times higher resolution, allowing infrared imaging of larger samples, in less time, with unprece­dented detail. “Infrared-optical hybrid micro­scopy is widely compatible with conven­tional microscopy in biomedical appli­cations,” Schnell said. “We combine the ease of use and universal availa­bility of optical micro­scopy with the wide palette of infrared molecular contrast and machine learning. And by doing so, we hope to change how we routinely handle, image and understand micro­scopic tissue structure.”

The researchers plan to continue refining the compu­tational tools used to analyze the hybrid images. They are working to optimize machine-learning programs that can measure multiple infrared wave­lengths, creating images that readily distin­guish between multiple cell types, and integrate that data with the detailed optical images to precisely map cancer within a sample. They also plan to explore further appli­cations for hybrid microscope imaging, such as forensics, polymer science and other biomedical appli­cations.

“It is very intriguing what this additional detail can offer in terms of pathology diagnoses,” Bhargava said. “This could help speed up the wait for results, reduce costs of reagents and people to stain tissue, and provide an all-digital solution for cancer pathology.” (Source: U. Illinois)

Reference: M. Schnell et al.: All-digital histopathology by infrared-optical hybrid microscopy, Proc. Nat. Ac. Sc., online 3 February 2020; DOI: 10.1073/pnas.1912400117

Link: Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana–Champaign, Urbana, USA

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