Microfluidics as a Fast Technique to Evaluate Antiviral Activity in Real Time

Significance 

Viruses carry around an outer shell of proteins called a capsid. The proteins act like a lockpick, attaching to and prying open a cell’s membrane. The virus then hijacks the cell’s inner workings, forcing it to mass produce the virus’s genetic material and construct many, many viral replicas. Much like popcorn kernels pushing away the lid of an overfilled pot, the new viruses explode through the cell wall. And the cycle continues with more virus lockpicks on the loose.

Watching the viral infection cycle and monitoring its stages is crucial for developing new antiviral drugs and gaining better understanding of how a virus spreads. Dielectrophoresis happens when polarizable cells get pushed around in a nonuniform electric field. The movement of these cells is handy for diagnosing diseases, blood typing, studying cancer and many other biomedical applications. When applied to studying viral infection, it’s important to note that viruses have a surface charge, so within the confined space in a microfluidic device, dielectrophoresis reveals the electric conversation between the virus capsid and the proteins of a cell membrane.

The technique uses microfluidics — the submillimeter control of fluids within a precise, geometric structure. On what is basically a tricked-out microscope slide, chemical engineers led by Professor Adrienne Minerick from Michigan Technological University have been able to manipulate viruses in a microfluidic device using electric fields. The study, published in Langmuir, looks at changes in the cell membrane and gives researchers a clearer idea of how antivirals work in a cell to stop the spread of infection.

Traditional techniques such as fluorescent labeling for different stages, imaging, checking viability. The problem is that these techniques are an indirect measure. Our tools look at charge distribution, so it’s heavily focused on what’s happening between the cell membrane and virus surface. The authors discovered with greater resolution when the virus actually goes into the cell. The researchers studied the interaction between the virus and cell in relation to time using microfluidic devices. They showed it is possible to see time-dependent virus-cell interactions in the electric field.

The cells in the microfluidic device dance around, shifting into distinct patterns with a dielectric music cue. There needs to be the right ratio of virus to cells to watch infection happen — and it doesn’t happen quickly. The study runs in 10-hour shifts, following the opening scenes of viral attachment, a long interlude of intrusion, and eventually the tragic finale when the new viruses burst out, destroying the cell in the process.

Before they burst, cell membranes form structures called blebs, which change the electric signal measured in the microfluidic device. That means the dielectrophoresis measurements grant high-resolution understanding of the electric shifts happening at the surface of the cell through the whole cycle.

Viral infections are top of mind right now, but not all viruses are the same. While microfluidic devices that use dielectrophoresis could one day be used for on-site, quick testing for viral diseases like COVID-19, the Michigan Tech team focused on a well-known and closely studied virus, the porcine parvovirus (PPV), which infects kidney cells in pigs.

That’s because glycine likely interrupts the new capsid formation for the replicated viruses within the cell itself. While that specific portion of the viral dance happens behind the curtain of the cell wall, the dielectric measurements show a shift between an infected cycle where capsid formation happens and an infected cell where capsid formation is interrupted by glycine. This difference in electrical charge indicates that glycine prevents the new viruses from forming capsids and stops the would-be viral lockpickers from hitting their targets.

This new view of the interactions between virus capsids and cell membranes could speed up testing and characterizing viruses, cutting out expensive and time-consuming imaging technology. Perhaps in a future pandemic, there will be point-of-care, handheld devices to diagnose viral infections and we can hope medical labs will be outfitted with other microfluidic devices that can quickly screen and reveal the most effective antiviral medications.

Microfluidics as a fast technique to Evaluate Antiviral Activity in real time - Medicine Innovates

About the author

Adrienne R. Minerick

Dean, College of Computing
Professor, Chemical Engineering
PhD, Chemical & Biomolecular Engineering, University of Notre Dame du lac (USA)

Adrienne R. Minerick joined the faculty at Michigan Tech as an Associate Professor in 2009 and was promoted to Professor in 2015.  In addition to the listed titles, she also serves as an Affiliated Professor with the Department of Biomedical Engineering at Michigan Tech.

Minerick’s primary area of research is electrokinetics with a focus on medical microdevices, blood cell dynamics, and point of care diagnostics. Her group’s primary area of specialty is dielectrophoresis which utilizes nonuniform AC fields to manipulate polarizable cells and other dielectric biomaterials.

She has received numerous honors and awards, including the distinction of Fellow of AAAS (American Association for the Advancement of Science), a National Science Foundation 2007 CAREER Award, the 2011 Raymond W. Fahien Award, Chemical Engineering Division, American Society of Engineering Education (ASEE), Michigan Tech’s Fredrick D. Williams Instructional Innovation Award, a New Investigator Research Award from Sigma Xi Chapter, one from ASEE-SE, and was the recipient of the Ralph E. Powe Junior Faculty Award, Oak Ridge Associated Universities. She and her students have published over 70 book chapters, archival journal publications or proceedings articles and earned 23 best paper/presentation awards.

Minerick previously served as the President of the American Electrophoresis Society (www.aesociety.org) and on the American Society for Engineering Education’s (ASEE) Board of Directors as First Vice President and Professional Interest Council (PIC) I Chair. She also chaired ASEE’s National Diversity Committee. Her research and service interests regularly intersect and involve underserved individuals with an emphasis on research experiences to increase engagement and retention.

Reference

Sanaz Habibi, Pratik U. Joshi, Xue Mi, Caryn L. Heldt, Adrienne R. Minerick. Changes in Membrane Dielectric Properties of Porcine Kidney Cells Provide Insight into the Antiviral Activity of Glycine. Langmuir, 2020; 36 (29): 8344 DOI: 10.1021/acs.langmuir.0c00175

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