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Clinical Laboratories and Pathology Groups

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Nano-Optic Endoscope Offers Anatomic Pathologists, Medical Laboratories Higher Resolution and Precision Optical Imaging

New metalens technology from MGH and SEAS researchers gives greater endoscopic optical imaging resolution and sample detail for anatomic pathologists performing diagnostics

Anatomic pathologists and clinical laboratories know that biopsy samples are necessary to diagnose many diseases. But, current endoscopic imaging techniques used by physicians sometimes fail to clearly visualize disease sites. Consequently, biopsies collected during these procedures may make it harder for pathologists and physicians to diagnose certain diseases and health conditions.

Now, a combined team of endoscopic imaging experts at Massachusetts General Hospital (MGH) and flat metalens developers at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed “a new class of endoscopic imaging catheters—termed nano-optic endoscopes—that overcomes the limitations of current systems.”

That’s according to an article in Nature Photonics that reported on the research team’s study, published in

These nano-optics involved “flat metalenses” that promise to sharpen clarity and increase resolution of endoscopic imaging technology In turn, this contributes to more accurate pathology diagnostics and improve patient outcomes, while furthering the aims of precision medicine.

“Metalenses based on flat optics are a game changing new technology because the control of image distortions necessary for high resolution imaging is straightforward compared to conventional optics, which requires multiple complex shaped lenses,” Federico Capasso, PhD, Robert L. Wallace Professor of Applied Physics and Vinton Hayes Senior Research Fellow in Electrical Engineering at SEAS, and co-senior author of the study paper, told Nature Photonics. “I am confident that this will lead to a new class of optical systems and instruments with a broad range of applications in many areas of science and technology.”

The image above shows a flat metalens taken using a scanning electron microscope. Anatomic pathologists and medical laboratories will benefit from the better quality biopsy specimens collected because of the sharper clarity and increased resolution of endoscopes built with the new nano-optics. (Photo copyright: Harvard SEAS.)

Researchers demonstrated the nano-optic endoscope’s ability to deeply penetrate and capture images at high resolutions in various tissues, including:

  • Swine and sheep airways;
  • Human lung tissue; and,
  • Fruit flesh.

In the human lung tissue, “[T]he researchers were able to clearly identify structures that correspond to fine, irregular glands indicating the presence of adenocarcinoma, the most prominent type of lung cancer,” according to

Improving Endoscopic Imaging through Metalenses

The improved image resolution is due to the flat metalens configuration. “Currently, we are at the mercy of materials that we have no control over to design high-resolution lenses for imaging,” Yao-Wei Huang, PhD, Post-Doctoral Fellow at Harvard’s John A. Paulson School of Engineering and Applied Sciences and co-first author of the paper, told

Yao-Wei Huang, PhD (above), is a Post-Doctoral Fellow at Harvard’s John A. Paulson School of Engineering and Applied Sciences and co-first author of the study paper. “The main advantage of the metalens is that we can design and tailor its specifications to overcome spherical aberrations and astigmatism and achieve very fine focus of the light. As a result, we achieve very high resolution with extended depth of field without the need for complex optical components.” (Photo copyright: Harvard School of Engineering and Applied Sciences.)

The researchers note that current endoscopes using gradient-index (GRIN) lens-prism configurations and angle-polished ball lenses are used in a range of clinical applications due to their basic design. However, this benefit comes with shortfalls. “The ability of the nano-optic endoscope to obtain high-resolution images of sub-surface tissue structures in vivo is likely to increase the clinical utility of OCT [optical coherence tomography] in detection, diagnosis, and monitoring of diseases,” they state in their paper.

“The ability to control other properties of output light, such as the polarization state, enables a host of other applications—implausible to achieve using conventional catheters,” they continue. “Several tissues—such as smooth muscle, collagen (either innate or in fibrosis), and blood vessels—have constituent structures highly organized in one particular direction. Polarization-sensitive imaging can differentiate these structures from surrounding tissue by detecting their innate birefringence and optic axis.”

They further note that nano-optic endoscopes may yield benefits to other endoscopic optical imaging modalities such as confocal endomicroscopy.

Additional clinically-oriented studies will be required to assess how nano-optic endoscopes can elevate the capabilities of endoscopic OCT in examining fine pathological changes in luminal tissues.

Implications for Clinical Laboratories and Pathology Groups

The technology is still in the research stage with more trials needed to confirm the viability and accuracy of the approach. “This preclinical evaluation of the nano-optic endoscope indicated no significant flaws in the design for in vivo endoscopic imaging,” researchers note.

However, should nano-optic catheters gain clearance and change the endoscopy landscape as researchers predict, medical laboratories and pathologists might enjoy higher resolution images with greater information of the sample site—both key components of accurate diagnosis.

“Clinical adoption of many cutting-edge endoscopic microscopy modalities has been hampered due to the difficulty of designing miniature catheters that achieve the same image quality as bulky desktop microscopes,” Melissa Suter, PhD, Assistant Professor of Medicine at MGH and Harvard Medical School (HMS) and co-senior author of the study told Nature Photonics. “The use of nano-optic catheters that incorporate metalenses into their design will likely change the landscape of optical catheter design, resulting in a dramatic increase in the quality, resolution, and functionality of endoscopic microscopy. This will ultimately increase clinical utility by enabling more sophisticated assessment of cell and tissue microstructure in living patients.”

This research project at Massachusetts General Hospital and Harvard John A. Paulson School of Engineering and Applied Sciences is another example of how advances in technologies unrelated to surgical pathology can eventually contribute to improvements in how pathologists diagnose disease and help physicians identify the most promising therapies for their patients.

—Jon Stone

Related Information:

Nano-Optic Endoscope Sees Deep into Tissue at High Resolution

Nano-Optic Endoscope for High-Resolution Optical Coherence Tomography In Vivo

Nano-Optic Endoscope Allows High-Resolution Imaging

High-Resolution Nano-Optic Endoscope for Better Disease Detection

UC Davis Researchers Develop Microscope That Uses Ultraviolet Light for Diagnosis, Eliminates Need for Traditional Histology Slide Preparation

MUSE microscope speeds up some anatomic pathology laboratory processes and removes exposure to toxic fixative chemicals

Because they handle tissue specimens, histotechnologists, anatomic pathologists, and hospital nurses are exposed to deadly chemicals such as formaldehyde, formalin, Xylene, and Toluene. The risks associated with these chemicals has been covered regularly by Dark Daily as recently as 2018 and as far back as 2011. (See, “Europe Implements New Anatomic Pathology Guidelines to Reduce Nurse Exposure to Formaldehyde and Other Toxic Histology Chemicals,” January 3, 2018; and, “Health of Pathology Laboratory Technicians at Risk from Common Solvents like Xylene and Toluene,” July 5, 2011.)

Now, scientists at the University of California at Davis (UC Davis) have developed a microscope that uses ultraviolet light (UV) to illuminate tissue samples. The UV microscope removes the need for traditional histology processes involved with preparation of tissue to produce conventional slides and makes it possible for anatomic pathologists to evaluate tissues without formalin fixation, according to a UC Davis news release.

“Here, we introduce a simple, non-destructive slide-free technique that, within minutes, provides high-resolution diagnostic histological images resembling those obtained from conventional hematoxylin and eosin histology,” the researchers wrote in their paper, published in Nature Biomedical Engineering.

High-resolution Biopsy Images in Minutes

The UV microscope relies on technology that UC Davis researchers dubbed MUSE, which stands for Microscopy with Ultraviolet Surface Excitation. According to the researchers, MUSE produces high-resolution images of biopsies and other fresh tissue samples that are ready for a pathologist’s review within minutes.

“MUSE eliminates any need for conventional tissue processing with formalin fixation, paraffin embedding, or thin-sectioning. It doesn’t require lasers, confocal, multiphoton, or optical coherence tomography instrumentation. And the simple technology makes it well-suited for deployment wherever biopsies are obtained and evaluated,” stated Richard Levenson, MD, MUSE Microscopy CEO, Professor, and Vice Chair for Strategic Technologies in the Department of Pathology and Laboratory Medicine at UC Davis, in the news release.

Ultraviolet microscopy is distinguished by its ability to magnify samples and enable views with greater resolution. This is due to the shorter wavelength of ultraviolet light, which improves image resolution beyond the diffraction limit of optical microscopes using normal white light, according to News Medical.

The unique ultraviolet light microscope tool may soon enable clinical laboratories and anatomic pathology groups to accurately report on biopsies to physicians and patients faster, for less money, and without exposure to deadly chemicals. This would be timely considering the pressure on the pathology industry to switch to value-based reimbursement from fee-for-service billing, and to embrace personalized medicine.

Richard Levenson MUSE UC Davis

“It has become increasingly important to submit relevant portion of often tiny tissue samples for DNA and other molecular functional tests,” notes Richard Levenson, MD, MUSE Microscopy CEO, Professor, and Vice Chair for Strategic Technologies in the Department of Pathology and Laboratory Medicine at UC Davis, shown above with MUSE. “Making sure that the submitted material actually contains tumor in sufficient quantity is not always easy and sometimes just preparing conventional microscope slices can consume most of or even all of small specimens. MUSE is important because it quickly provides images from fresh tissue without exhausting the sample.” (Photo and caption copyright: UC Davis.)

MUSE is being commercialized and investors sought by MUSE Microscopy, Inc.

Traditional Microscopy is Time-Consuming, Hazardous, Expensive

Light microscopy, a time-honored technology, has been available to pathologists for more than 200 years. It is the cornerstone for cancer diagnostics and pathology, the UC Davis researchers acknowledged. But it requires time-consuming and expensive processes, which are especially glaring in a resource-challenged healthcare industry, they pointed out.

“Histological examination of tissues is central to the diagnosis and management of neoplasms and many other diseases. However, commonly used bright-field microscopy requires prior preparation of micrometer-thick tissue sections mounted on glass slides—a process that can require hours or days, contributes to cost, and delays access to critical information,” they wrote in their paper.

“MUSE promises to improve the speed and efficiency of patient care in both state-of-the art and low-resource settings, and to provide opportunities for rapid histology in research,” they continued.

No Histology Slide Preparation Needed

MUSE developers also called attention to the use of hazardous chemicals, such as formalin, in lab processes, which has been linked to cancers including myeloid leukemia, nasopharyngeal cancer, and sinonasal cancer, according to a National Academy of Sciences report. Still, more than 300 million slides are prepared in the US each year at a cost of several billion dollars to the healthcare industry, according to the MUSE Website.

MUSE, however, penetrates tissue samples by using ultraviolet light at short wavelengths—below the 300-nanometer range. The MUSE ultraviolet microscope can reach several microns-deep into tissues.

That’s enough, the researchers claim, to be comparable with the thickness of tissue slices anatomic pathologists use with traditional microscope slides. However, MUSE requires no conventional tissue processing associated with histology slides.

How Does it Work?

MUSE is comprised of an optical system with UV light-emitting diodes (LEDs), a UV compatible stage, and a conventional microscope. That’s according to Photonics Online, which described the process:

  • “UV light at 280 nanometer spectral range illuminates about one square millimeter of specimen;
  • “Surface is limited to a few nanometers deep to make high-contrast images possible;
  • “Excitation light, at sub-300 nanometer spectral region, elicits bright emission from tissue specimens;
  • “Specimens, which were stained with conventional florescent dyes, emit photons;
  • “Photons are captured using glass-based microscope optics;
  • “A Python programing language solution, with a graphics unit, converts MUSE images in real-time;
  • “Images are comparable to the hematoxylin and eosin versions histologists and pathologists are accustomed to.”

The result, according the MUSE website, “is stunning detailed images conveying a degree of resolution, structure, and depth unachievable until now by any single technology.”

Other Alternative Histology Processes Under the Microscope

MUSE is not the only approach being studied that could create cellular images without sectioning tissue samples. Anatomic and histopathology laboratory leaders looking to differentiate their labs should keep watch on the development of MUSE and other alternatives to current histology methods, especially once these new devices become green-lighted by the Food and Drug Administration (FDA) for use in patient care.

—Donna Marie Pocius

Related Information:

Microscope That Uses Ultraviolet Instead of Visible Light Emerging as Powerful Diagnostic Tool

Microscope with Ultraviolet Surface Excitation for Rapid Slide-Free Histology

Ultraviolet Microscope to Dramatically Speed-up Lab Tests

What is Ultraviolet Microscopy?

Europe Implements New Anatomic Pathology Guidelines to Reduce Nurse Exposure to Formaldehyde and Other Toxic Histology Chemicals

National Academy of Sciences Confirms That Formaldehyde Can Cause Cancer in a Finding That Has Implications for Anatomic Pathology and Histology Laboratories

Health of Pathology Laboratory Technicians at Risk from Common Solvents like Xylene and Toluene