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Osaka Researchers Developing More Sensitive Terahertz Chip for Medical Diagnostics


NEW YORK (360Dx) – Researchers at Osaka University have built a diagnostic proof-of-concept platform using a nonlinear optical crystal that emits terahertz waves and uses their closeness to a biological sample in a microchannel to achieve better sensitivity.

In a study published recently in the journal APL Photonics, they demonstrated the use of nonlinear optical crystal-based terahertz microfluidic chips for terahertz-time-domain spectroscopy measurements of liquid inside a microchannel.

The system consists of a microfluidic chip that has been used to measure glucose levels in blood, Masayoshi Tonouchi, one of the test's developers and a professor at Osaka University, said in an interview.

The platform consists of a terahertz radiation point source, a single microchannel, and a few arrays of metaatoms, which are the elementary units of metamaterials. Terahertz radiation generated in the nonlinear optical chip underneath and close to the microchannel couples with the metaatoms. The system measures the concentration of biological solutions based on changes in the resonant frequency and peak attenuation of terahertz waves.

The researchers concluded that the technique, demonstrated with water as a sample, opens the door to analyzing biological samples with terahertz waves and accelerates development of lab-on-chip devices, which are being explored for several applications including medical diagnostics.

They would need to further improve upon its sensitivity for some diagnostic applications, and the platform will require extensive testing on clinical blood samples to prove its analytical validity and clinical utility, Tonouchi said. However, it has the potential to be developed as a diagnostic test for several applications, he added.

Joo-Hiuk Son, a researcher in the department of physics at the University of Seoul, said in an interview that terahertz technology "will play a significant role in future medical diagnostics because many characteristic energies of biomolecules lie in the terahertz region."

Among the most important outcomes of the Osaka team's system is that it enables measuring molecules in the range of a few tens of femtomoles, which means that "the technique can measure small changes in molecules, cells, and organisms," said Son, the author of the book Terahertz Biomedical Science & Technology, which focuses on emerging terahertz developments for biomedical applications. One potential application for the Osaka researchers' device is the diagnosis of cancers using biofluids, he said.

Tonouchi said that his team has improved the sensitivity of terahertz diagnostic devices one hundredfold compared to the most advanced existing terahertz diagnostic devices and reached a level of performance where they can develop it for clinical diagnostic applications. With the technique, they detected solution concentrations of several femtomoles in volumes of less than one nanoliter, a level of sensitivity that along with biofluid requirement imbues it with the potential for use as a minimally invasive clinical blood test.

Its sensitivity is comparable to that of a standard, commercial fluorescence-based testing system, such as an ELISA platform that use antigen-antibody reactions, he said.

They have correlated their terahertz measurements with data from a commercially available glucometer to prove its potential to detect glucose in human blood, which Tonouchi said has potential in diabetes monitoring.

"The extreme sensitivity and low-volume requirements are phenomenal," and among the most important findings of the study, Andrea Markelz, a professor of physics at the University at Buffalo, said in an interview. "The near-field chip approach with such low volumes and high sensitivity could be used for a broad variety of low-concentration solutes," she added.

The Osaka researchers said that they expect that the technique could eventually be applied to early and rapid detection of several diseases, including not only cancers but also diabetes and infectious diseases such as influenza. To detect biomarkers and viruses that are only minimally present and difficult to trace in body fluids, the group would need to improve the system's sensitivity, which could be achieved by optimizing materials and device structures, Tonouchi said.

He noted that the terahertz region provides "important information" that clarifies biological reaction dynamics, including hydrogen bond and hydrophobic interactions. "Since DNA is bound to hydrogen, various functionalities can be examined by observing such weak interaction energy," he said. "We believe that this system enables simpler and more quantitative measurement of living samples by hybridizing them in a chip."

Among its potential advantages is the likelihood that it could detect diseases in exceptionally small volumes of blood or other body fluids and reduce the discomfort and pain associated with tissue biopsies, the researchers said.

Tonouchi noted that, importantly, their platform could enable development of diagnostic tests that wouldn't require antibody labeling.

Label-free methods have some unique advantages, "such as high sensitivity, small working volumes, low damage to analytes, and easy on-chip integration," according to researchers at the Third Military Medical University in Chongqing, China. Labeling is time-consuming and can alter the intrinsic properties of analytes, they said.

Last year, the group summarized their findings about potential applications of new generation label-free technologies in the clinical laboratory in the journal Frontier in Laboratory Medicine. They focused on terahertz spectroscopy, Raman spectroscopy, biochips, microarrays, quartz crystal microbalance devices, and mass spectrometers.

In clinical use, the terahertz platform would be part of an in vitro diagnostic system for testing, but the Osaka University team is also using the technique to develop a system for high-resolution imaging of tumor cells.

Different disease conditions in cells have specific diffractive indices that can be captured by the terahertz wave system, Tonouchi said. "We are not sure yet how sensitive this technique is in detecting cancers, but we know that in the imaging application, we can detect whether a tissue is normal or cancerous," he said. It usually takes many hours to prepare a sample to detect cancers or other diseases, he noted. With a terahertz diagnostic device, it could be possible to conduct this analysis onsite by taking an image of tissue cells on a glass slide.

Tonouchi said that although the group at present does not have a clear plan to commercialize the technology, it is seeking a partner company that would help it to develop a commercial diagnostic test, and it expects that a commercial system used by laboratories could be available within three years.

Generally, to move the field of terahertz clinical diagnostics along, it will be important "to establish biosensors and fundamental measuring technology and protocols that can measure trace amounts of a solution with high-speed and high-sensitivity," he said. "In order to solve these problems, it is necessary for researchers to develop compact and less expensive terahertz light sources, as well as array detectors capable of real-time measurement at room-temperature operation."

Several research groups have been showing promising progress in recent years, he said.

In 2016, Son and his colleagues presented the results of a study in Scientific Reports through which they detected terahertz molecular resonance fingerprints caused by the methylation of cancer DNA. They had extracted the DNA from living cell lines and then quantified them to distinguish cancer types.

"Resonance signals can be quantified to identify types of cancer cells with a certain degree of DNA methylation," they noted, adding that fingerprints of cancer DNA in the terahertz region can be used "for the early diagnosis of cancer cells at the molecular level."

In May 2017, Son and his colleagues noted in the IEEE Journal of Selected Topics in Quantum Electronics that cancer imaging using terahertz spectroscopy has the potential to overcome the drawbacks of existing cancer imaging techniques because of the unique properties of terahertz radiation.

In August last year, researchers in the Korea Institute of Science and Technology in Seoul published a study in which they used nanosized metamaterials in a sensing chip as part of a terahertz spectroscope that characterized several types of Avian influenza viruses.

However, over the years, terahertz-wave technology for medical diagnostics and other applications has advanced slowly. 

A major challenge in getting terahertz technologies into commercial diagnostic applications has been the "delay in the development of terahertz light sources and detectors and establishment of novel terahertz measurement techniques," Tonouchi said. "In addition, due to the strong absorption of terahertz waves into water, it has been difficult to quickly measure biological samples that are collected from patients."

Biomolecular materials optical properties in the terahertz frequency range were mostly unknown in the 1990s, when access to this frequency range for diagnostic applications "essentially began," said Markelz, who specializes in terahertz optical techniques and the characterization of protein dynamics. For other electromagnetic frequency ranges, including near infrared and ultraviolet, extensive spectroscopic studies laid the groundwork for applications, she said. 

"During the '60s and '70s, an irrational exuberance towards fundamental cataloging appeared to exist," Markelz said. "It seems that a general cynicism has set in for new instrument technology, and unfortunately THz development is one of the fields that is suffering for it." 

There have been a variety of characterization papers for terahertz wave technology in diagnostic applications, but "one cannot build a reliable diagnostic on these," she said. 

Nonetheless, the use of terahertz waves in the measurement of substances that are well characterized is occurring in industrial process monitoring, she said. A simple device that diagnoses substances that are well characterized, such as glucose, could be "enough to get things rolling" for the Osaka team, she said.

In developing a commercial platform, reducing production costs could be among the challenges that the Osaka researchers will need to overcome, Markelz said.

The University of Seoul's Son said that terahertz technology is "rather novel" in the context of medical diagnostics, and many clinical trials should be performed before it could be commercially available. However, due to rapid advances and cost reductions, a commercial terahertz medical diagnostic device could emerge in about five years, he noted.