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Early respiratory virus detection research among Royal Society of Chemistry’s top citations

6/23/2022 10:06:55 AM Kim Gudeman, HMNTL

In 2019, researchers at the University of Illinois Urbana-Champaign were working on a rapid test that could detect horse respiratory viruses in less than 30 minutes using a nasal swab and a smartphone. When the COVID-19 outbreak began later that fall, the team was able to pivot quickly to include the SARS-CoV-2 virus among the pathogens that could be identified.

Covid virus
Covid virus

Their early study on COVID-19 was published in Lab on a Chip in April 2020, and in 2021 that paper was among the top 3% most cited Royal Society of Chemistry publications. It has been cited in many peer-reviewed journals, including ACS Nano and Scientific Reports.

“The timing was really good,” said Brian Cunningham, the Intel Alumni Endowed Chair in Electrical and Computer Engineering and one of the study’s authors. “We were already working on how to use mRNA to detect viruses quickly with an inexpensive device that everyone has (a smartphone), so we were able to transition to COVID-19 easily. Our paper may have been the first to show this capability.”

Brian Cunningham
Holonyak Lab faculty and study co-leader Brian Cunningham

Before the pandemic began, the team was already testing the diagnostic tool on horses located on UIUC’s Veterinary Medicine campus. Horses and other animals experience a viral transmission process similar to that of humans, and the interventions for suppressing disease spread – quarantining and distancing from others – are much the same. When the COVID-19 outbreak occurred, the scientists were able to parlay their work to include the SARS-CoV-2 strain.

Cunningham said the research’s magic sauce was in the detection process. Unlike polymerase chain reaction (PCR) tests, which are often considered the gold standard for virus detection, the UIUC test focused on nucleic acids. For that reason, the team was able to create a test that could work with samples at the same temperature for 30 minutes. PCR tests, on the other hand, must cycle among various temperatures – one reason why they require certain lab conditions and special equipment.

“Our test gives an answer really quickly,” Cunningham said. “And instead of having to use really expensive diagnostic tools in a laboratory, we were able to get similar results from a smartphone in the field.”

Rashid Bashir
Holonyak Lab faculty and study co-leader Rashid Bashir.

In addition to Cunningham, the authors include Grainger Engineering Dean Rashid Bashir, Animal Sciences Professor Matthew Wheeler, Bioengineering Research Scientist Anurup Ganguli, and graduate students Fu Sun (first author), Judy Nguyen, Ryan Brisbin, Krithika Shanmugam, and David L. Hirschberg. David M. Nash also contributed. The initial work was funded by the National Science Foundation.

Cunningham said that since the paper’s publication, his group has developed a second method for detecting COVID-19 and other viruses. While the original method broke the virus open to access its nucleic acid, the new process can detect the intact virus.

“The new test is better, faster, and more sensitive and can detect COVID-19 in five minutes at room temperature,” Cunningham said. “It’s a new technique, and we’re really excited about its possibilities.”

1-minute cancer test using magnetic-plasmonic nanoparticles

January 27, 2022
By: Alisa King-Klemperer

The detection and quantification of cancer-associated molecular biomarkers in body fluids, or liquid biopsies, prove minimally invasive in early cancer diagnostics. Researchers at the University of Illinois Urbana-Champaign have developed an approach that accelerates the detection of cancer biomarkers in samples taken at the time and place of patient care.

 

Computer rendering of the magnetic activate capture+digital counting approach for accelerated digital biodetection
Computer rendering of the magnetic activate capture+digital counting approach for accelerated digital biodetection.

 

The study, published in ACS Nano, focused on the detection of a group of molecular biomarkers called microRNAs (miRNAs), small, single-stranded and noncoding RNAs that play important roles in gene expression and regulation. More importantly, miRNAs have been linked to certain cancer types and stages and as such, have garnered increased attention.

“Since tumor-specific mutations in miRNAs can be linked to tumor progression and metastasis, we can use miRNAs for early cancer diagnostics and therapy selection in the future,” said Congnyu Che, bioengineering graduate student in the Cunningham lab and first author of the paper. “Conventional detection methods take up to several hours for the person to get the result so our motivation was to accelerate the response time and make it shorter.”

Previously, the Cunningham group developed a technique to capture miRNA biomarkers, called Photonic Resonator Absorption Microscopy, that is capable of visualizing gold nanoparticles bound to target miRNAs. Using gold-only nanoparticles, it would take between 1-2 hours before the nanoparticles found their way to the biosensor. To accelerate the process, Che synthesized magnetic-plasmonic nanoparticles that incorporated iron materials that could then be attracted by a stationary magnet placed under the biosensor. The detection time was reduced to just one minute.

“Our approach has a one-minute response time, which means that the patient or doctor only waits for one minute before finding out the test result,” said Che.

“If you have a simple, fast and sensitive test like that, it can be used for detecting cancer, monitoring cancer treatment effectiveness, and following up with treatment,” said study leader Brian Cunningham (CGD Director/MMG), the Intel Alumni Endowed Chair of Electrical and Computer Engineering. “We envision this method being used in a health clinic so you wouldn’t have to take a sample, send it to a lab, and wait several days.”

In the study, the researchers focused on miRNAs associated with advanced prostate cancer since they have a collaboration with prostate cancer experts at the Huntsman Cancer Institute in Utah. They demonstrated a faster detection time and high selectivity when using magnetic-plasmonic nanoparticles to detect the miRNAs in human serum.

“This approach provides much more rapid sample-to-answer analysis of miRNA biomarkers that are used in cancer, nutrition, cardiac health, and maternal health diagnostics in point-of-care scenarios,” said Cunningham.

This work was supported by the IGB, the National Institutes of Health, the National Science Foundation, and the Zhejiang University ZJU-UIUC Joint Research Center.

 


January 27, 2022
By: Alisa King-Klemperer
Photos By: Alex David Jerez Roman, Beckman imaging technology group

Direct Detection of Intact SARS-CoV-2 with PCR Sensitivity

New label-free detection technique digitally counts intact SARS-CoV-2 virus particles in saliva or exhaled breath

As health and research institutions continue to rapidly develop new methodologies for detecting SARS-CoV-2, researchers from the Holonyak Micro & Nanotechnology Laboratory have found themselves at both forefronts of discovery and featured on the cover of the Journal of the American Chemical Society with their paper: Label-free Digital Detection of Intact Virions by Enhanced Scattering Microscopy.

Label-free detection, an approach that utilizes a biosensor and detection instrument for viral load monitoring, is a solution that can capture and digitally count intact virus particles in saliva or exhaled breath to provide lower cost and reduced time to diagnose an infection.

Currently, the most widely used SARS-CoV-2 PCR testing method is the PCR assay, which uses enzymatic amplification to make many copies of a specific section of the virus’s RNA, which requires extraction of the viral genome and a complex laboratory procedure.  Instead, the new approach uses a specially designed nucleic acid molecule, called an “aptamer” attached to a biosensor that selectively recognizes one of the proteins on the virus outer surface, and captures it in a single step at room temperature, with no other reagents required.  Once captured, the viruses are counted, using a newly invented form of microscopy, that generates images from laser light that scatters from each captured virus.

“Our technique requires only the saliva sample, and avoids the need for any additional reagents, thus we expect the cost for a test to be significantly reduced and the overall process to be greatly simplified (less labor-intensive),” said co-author Nantao Li, a graduate student in electrical and computer engineering. “In addition, the aptamers we used can selectively differentiate between active viruses from inactive ones, thus providing more robustness for diagnosis results. Conventional techniques, such as PCR, detect the viral RNA sequence which can remain in bodily fluids even after infectious viruses are no longer present.”

To detect and count the captured viruses, the team recently invented a new imaging approach called Photonic Resonator Interferometric Microscopy (PRISM). PRISM uses a photonic crystal biosensor surface to enhance light scattering from virus particles. The photonic crystal is a nanostructured surface that provides two effects. First, it enables each virus to scatter more light from an illuminating laser, which increases their signal contrast.  Secondly, the photonic crystal directs the scattered light toward the microscope objective – allowing a larger fraction of the scattered light to be collected.

While label-free digital detection can be a promising alternative to traditional SARS-CoV-2 detection, principal investigator Brian Cunningham believes this approach can be widely applicable to other areas.

“We are already making plans soon to perform viral load monitoring of HIV in plasma, and we are building a more portable version of the detection system that would be small and inexpensive enough to perform well in biology labs or diagnostic lab facilities,” said Cunningham, Intel Alumni Endowed Chair in Electrical and Computer Engineering.

Moving forward, the research team – comprised of principal investigators Brian Cunningham, Yi Lu, Xing Wang, and co-authors Xioajing Wang, Nantao Li, and Joseph Tibbs, are designing and implementing a new type of capture molecule that will reduce the detection time to a few minutes. They envision the future capability for a person to exhale into a device, and for exhaled virus particles to be captured on the sensor.

To read more about Label-free Digital Detection of Intact Virions by Enhanced Scattering Microscopy, you can find it published in the Journal of American Chemical Society here. 

New Point of Care Diagnostic Instrument for Cancer Biomarkers

October 18, 2021
By: Ananya Sen

Current medical diagnostics involve sending samples to laboratory facilities, which can be difficult and expensive. Researchers at the University of Illinois Urbana-Champaign have designed a desk-sized instrument that can make the same measurements at the location where the samples are collected.

For several years the Cunningham group has been developing microscopes that use photonic crystal biosensors—nanostructured glass surfaces that brightly reflect only one wavelength of light. “Although our original photonic crystal microscope is very versatile, it’s the size of a ping pong table,” said Brian Cunningham (CGD Director/MMG), the Intel Alumni Endowed Chair of Electrical and Computer Engineering. “We wanted to build a portable instrument that had the same detection capabilities. The new one we built can easily fit on a desk and costs around $7,000, compared to the non-portable microscope, which costs $200,000.”

The researchers had previously developed the larger photonic crystal microscope so that it could provide a strong contrast counting surface-attached gold nanoparticles, a feature that the portable version also shares. “The photonic crystals act like a mirror, but only for the color red. The gold nanoparticles are non-reflective and show up as dark spots,” Cunningham said. The microscopes can, therefore, be used to detect proteins or other biomarkers that are linked to the gold nanoparticles.

The portable versions use a red LED light, which gets reflected off the photonic crystal, and the image is captured by a webcam. “The system itself is quite easy to build and can be put together within a day,” said Nantao Li, a graduate student in the Cunningham lab and co-first author on the paper.

The portable microscope was used to detect specific microRNAs—small, single-stranded, non-coding RNAs—that are associated with prostrate cancer. Each gold nanoparticle was attached to a single-stranded piece of DNA, called the probe, which in turn was attached to pieces of single-stranded protector DNA. If the target miRNA sequence was present in the sample, it would displace the protector DNA, which would cause the nanoparticle to bind to the photonic crystal, according to Shreya Ghosh, a previous postdoctoral researcher in the Cunningham lab and the other co-first author of the paper.

Since almost every cancer has miRNAs associated with it, the microscope can, in theory, be used to detect different cancer types. “We are collaborating with researchers at the Mount Sinai Medical Center to diagnose lung cancer, and with Huntsman Cancer Institute to measure the effects of chemotherapy in prostate cancer,” Cunningham said. “We will also be working with Carle Hospital to detect miRNAs found in the blood of breast cancer patients.”

The researchers are working to lower the microscope cost even further. “We are trying to use smartphone cameras to capture the images. Our aim is to reduce the cost to less than $100,” Li said. They are also trying to build handheld versions of the microscope, which would consist of a box with an image sensor that can communicate wirelessly with a smartphone.

The Cunningham lab is currently seeking to establish a Center for Enhanced Biosensor Microscopy at the IGB, where they will be able to train researchers throughout the academic research community to use these instruments to detect any type of biomarker.

The study “A compact photonic resonator absorption microscope for point of care digital resolution nucleic acid molecular diagnostics” was published in Biomedical Optics Express. The work was funded by the National Institutes of Health, Jump ARCHES endowment through the Health Care Engineering Systems Center, Zhejiang University ZJU-UIUC Joint Research Center, Ronald H. Filler Scholarship for Cancer Scholars, and the Illinois Scholars in Undergraduate Research Scholarship.

Introducing PRISM: Photonic Resonance Interferometric Scattering Microscopy

CUNNINGHAM GROUP DEVELOPS MICROSCOPE TECHNIQUE TO DETECT INDIVIDUAL VIRUSES FOR POWER RAPID DIAGNOSTICS

CHAMPAIGN, Ill. — A fast, low-cost technique to see and count viruses or proteins from a sample in real time, without any chemicals or dyes, could underpin a new class of devices for rapid diagnostics and viral load monitoring, including HIV and the virus that causes COVID-19.

Researchers at the University of Illinois Urbana-Champaign described the technique, called Photonic Resonator Interferometric Scattering Microscopy, or PRISM, in the journal Nature Communications.

“We have developed a new form of microscopy that amplifies the interaction between light and biological materials. We can use it for very rapid and sensitive forms of diagnostic testing, and also as a very powerful tool for understanding biological processes at the scale of individual items, like counting individual proteins or recording individual protein interactions,” said Illinois ECE Professor and study leader Brian T Cunningham, the Intel Alumni Endowed Chair of electrical and computer engineering and a member of the Holonyak Micro and Nanotechnology Lab and the Carl R. Woese Institute for Genomic Biology at Illinois.

In optical microscopes, light bounces off any molecules or viruses it encounters on a slide, creating a signal. Instead of a regular glass slide, the PRISM technique uses photonic crystal: a nanostructured glass surface that brilliantly reflects only one wavelength of light. Cunningham’s group designed and fabricated a photonic crystal that reflects red light, so that the light from a red laser would be amplified.

“The molecules we are looking at – in this study, viruses and small proteins – are extremely small. They cannot scatter enough light to create a signal that can be detected by a conventional optical microscope,” said graduate student Nantao Li, the first author of the paper. “The benefit of using the photonic crystal is that it amplifies the light’s intensity so it’s easier to detect those signals and enables us to study these proteins and viruses without any chemical labels or dyes that might modify their natural state or hinder their activity – we can just use the intrinsic scattering signal as the gauge for determining if those molecules are present.”

PRISM for COVID-19 detection. At top, concept art. Bottom left, a microscope image of a single virus on the photonic crystal surface. Bottom right, a PRISM image with six viruses detected. Image courtesy of Nantao Li
PRISM for COVID-19 detection. At top, concept art. Bottom left, a microscope image of a single virus on the photonic crystal surface. Bottom right, a PRISM image with six viruses detected.
Image courtesy of Nantao Li

The researchers verified their technique by detecting the virus that causes COVID-19. PRISM detected individual coronaviruses as they traveled across the slide’s surface. The researchers also used PRISM to detect individual proteins such as ferritin and fibrinogen. The technique could allow researchers to study such biological targets in their natural states – watching as proteins interact, for example – or researchers could seed the surface of the photonic crystal slide with antibodies or other molecules to capture the targeted items and hold them in place.

“It takes 10 seconds to get a measurement, and in that time we can count the number of viruses captured on the sensor,” Cunningham said. “It’s a single-step detection method that works at room temperature. It is also fast, very sensitive and low cost. It’s very different from the standard way we do viral testing now, which involves breaking open the viruses, extracting their genetic material and putting it through a chemical amplification process so we can detect it. That method, called PCR, is accurate and sensitive, but it requires time, specialized equipment and trained technicians.”

Cunningham’s group is working to incorporate PRISM technology into portable, rapid diagnostic devices for COVID-19 and HIV viral load monitoring. The group is exploring prototype devices that incorporate filters for blood samples and even condensation chambers for breath tests.

“We are also going to use this as a research tool for biology and cancer,” Cunningham said. “We can use it to understand protein interactions that are parts of disease processes. We are interested in using it to detect these tiny vesicles that cancer cells shed, and to see what tissues they come from, for diagnosis, and also to study what cargo they are transporting from the cancer cells.”

The National Science Foundation and the National Institutes of Health supported this work. Cunningham is affiliated with the Beckman Institute and HMNTL.

 

Establishing the Center for Pathogen Diagnostics

9/30/2020, Kim Gudeman

With COVID-19 infecting more than 25.1 million worldwide to date, the pandemic has underscored the need for cost-effective, accurate, and quick diagnostics.

The University of Illinois, Urbana-Champaign and Zhejiang University are launching the Center for Pathogen Diagnostics (CPD) to create new detection systems that address limitations of current technologies, while leveraging the power of artificial intelligence and machine learning to analyze disease trends, analyze sensor data, and predict future outbreaks. The new devices – which will range from wearable sensors to mobile point-of-care devices to large laboratory instruments – will be able to detect pathogens that cause viral, bacterial, fungal, environmental, and food-borne illnesses.

“With COVID, we’re seeing the limitations of current best practices for virus detection,” said Brian Cunningham, the Intel Alumni Endowed Chair in the Department of Electrical and Computer Engineering at Illinois. “It takes too long to get results, and accuracy remains a concern. Instead of chemical testing, we’re interested in using new detection modalities, like detecting intact viruses, to create faster, more cost-effective diagnostics.”

The team, which is comprised of researchers at Illinois and ZJU, represents five “pillars” of pathogen diagnostic technologies. First, researchers will study the interactions between pathogens and host cells at the molecular level, which will provide targets for new pathogen detection platforms.

Second, the team will develop sample pre-processing techniques that enable the breakdown of cells and extraction of DNA and RNA, so that viruses and bacteria can be identified. This step will help researchers create a device capable, for example, of differentiating COVID-19 (SARS-CoV-2) from influenza, which, while both viruses, have features that can be used to distinguish them from each other.

Researchers also will create biosensors that are more sensitive, which will lower false negatives and positives, and be able to detect different variations of SARS-CoV-2. One important direction is development of mobile smartphone-based platforms that allow test results to be obtained immediately after gathering a sample, and the fabrication of microfluidic devices that automate the pre-processing of test samples before the detection step.

Finally, the team will use AI and machine learning algorithms to analyze data that is produced by the sensors, and to monitor health trends for public health officials. For example, AI could be used to provide better modeling for disease transmission or to reduce the number of physical tests needed in a community by making inferences about infection rates from a small subset of the population.

Transitioning the technology to the marketplace will be an important component of the center as well, says Cunningham.

“The purpose of the center is to do innovative research that actively improves global public health,” he said. “Commercialization is one of the outcomes that we’re working towards.”

The Center for Pathogen Diagnostics will be located in the Holonyak Micro & Nanotechnology Laboratory. In addition to Cunningham, the Illinois research team includes: Yang Zhao, HMNTL Director Xiuling Li, and Lav Varshney, electrical and computer engineering; Yi Lu, chemistry; Steven Blanke, microbiology; and Xing Wang, Holonyak Micro & Nanotechnology Lab. The ZJU team includes Shaowei Fang, Qingjun Liu, Chun Zhou, Huan Hu, and Yu Lin.

The new five-year, $1.5 million center is not the first collaboration between the two universities. In 2016, The Zhejiang University-University of Illinois at Urbana-Champaign Institute (ZJUI) was launched on ZJU’s international campus in Haining, China, about 120 km southwest of Shanghai. ZJU-UIUC Institute faculty teach and research in broad program themes of engineering and system sciences; information and data sciences; and energy, environment, and infrastructure sciences. The Center is one of three research efforts that was just funded through the ZJUI initiative.

“The Center for Pathogen Diagnostics is another great example of the fruitful partnership that Illinois enjoys with ZJUI,” said Dean Rashid Bashir of The Grainger College of Engineering. “We look forward to working with ZJUI on solving urgent problems that are relevant to the entire global community.”

Portable Smartphone COVID Test

As COVID-19 continues to spread, bottlenecks in supplies and laboratory personnel have led to long waiting times for results in some areas. In a new study, University of Illinois, Urbana-Champaign researchers have demonstrated a prototype of a rapid COVID-19 molecular test and a simple-to-use, portable instrument for reading the results with a smartphone in 30 minutes, which could enable point-of-care diagnosis without needing to send samples to a lab.

The paper can be found on the Nanosensors Group “Publications” page, and at the Proceedings of the National Academy of Sciences website:

https://www.pnas.org/content/early/2020/08/27/2014739117

The press release to this news story can be found at:

https://news.illinois.edu/view/6367/241622493

Using Photonics to Generate “Hot Electrons” that Catalyze Chemical Transformations

Researchers in Prof. Brian Cunningham’s Nanosensors Group at the University of Illinois, in collaboration with Prof. Singamaneni’s research group at Washington University, described a new approach for efficiently catalyzing chemical reactions using light, in the journal ACS Photonics.   The researchers harnessed a new approach for amplifying electromagnetic fields in nanometer-scale volumes by coupling the energy from a laser into a nanostructured photonic crystal surface.  The electromagnetic fields in the photonic crystal resonate with the laser’s wavelength, and when a metal nanoparticle is placed onto the photonic crystal, the electrons in the metal resonate as well.    A portion of the resonating electrons become more reactive than ordinary electrons, and are able to transfer to nearby chemical molecules, and thus catalyze specific chemical reactions.  The reactive electrons are often referred to as being “hot,” even though they are not hot in the temperature sense. The research shows that, by coupling  laser light to a photonic crystal, chemical reactions are driven forward with greater efficiency, allowing less energy to perform a process than possible without the photonic crystal.  Because the approach uses low illumination power that can be distributed over large surface areas, we envision the potential for optically driven chemical reactors.  The reactors would be only several micrometers in height, with transparent windows, an inlet for precursors, an outlet for products, and nanoparticle-coated photonic crystals comprising the upper and lower surfaces.

ECE graduate student Qinglan Huang and IGB Fellow Taylor Canady led the research, which was performed in the Holonyak Micro and Nanotechnology Laboratory.  The paper, entitled “Enhanced Plasmonic Photocatalysis through Synergistic Plasmonic–Photonic Hybridization“, by  Q. Huang, T.D. Canady, G. Gupta, N. Li, S. Singamaneni and B.T. Cunningham, can be found at:  ACS Photonics (2020).

Check out the final paper here: FINAL published ACS2020.

Digital Diagnostics Review Paper in Lab on a Chip

The Nanosensors Group from the University of Illinois at Urbana-Champaign published a Critical Review for the journal Lab on a Chip, entitled “Digital Resolution Biomolecular Sensing for Diagnostics and Life Science Research.”  The co-authors of the paper are Qinglan Huang, Nantao Li, Hanyuan Zhang, Congyu Che, Fu Sun, Yanyu Zhang, Taylor Canady,  and Brian Cunningham.  The paper reviews an important and very challenging frontier of the field of biosensing, where novel technologies are demonstrating the ability to digitally count molecules with single-unit precision. Through the use of enzymatic chemical reactions, nanoparticle tags, ultra-sensitive transducers, multiplexing detection instruments, and novel biochemistry, the reviewed technologies are finding applications in life science research, drug discovery, and diagnostics.

The paper can be found on the Nanosensors Group “Publications” page, and at the Lab on a Chip web site:

https://pubs.rsc.org/en/content/articlelanding/2020/lc/d0lc00506a#!divAbstract

 

 

Inexpensive, portable detector identifies pathogens in minutes

Editor’s notes:

To reach Brian Cunningham, call 217- 265-6291; email bcunning@illinois.edu.

The paper “Smartphone-based multiplex 30-minute nucleic acid test of live virus from nasal swab extract” is available online and from the U. of I. News Bureau. DOI: 10.1039/D0LC00304B