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New Breakthrough Could Lead to All-Purpose Biosensors

Illustration showing a laser beam and illuminated nanoparticles
Credit: Holger Schmidt, ECE Department, University of California Santa Cruz.
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A new signal processing technique may allow scientists to design “lab-on-a-chip” biosensors that can detect multiple analytes across vast concentration ranges simultaneously. Published in the journal Optica, the researchers say that this new technique could lead to breakthroughs in designing new all-purpose biosensors for medical testing. 

Moving away from single-analyte testing

Lab-on-a-chip testing devices are not a new invention. However, many of the devices that have been produced to analyze bioparticles – such as viral particles and DNA – are only able to focus on one type of analyte or one type of test at a time. When you look at the diversity of the different biomolecules present in the body, and the drastically different concentrations in which they are present, it is clear to see why previous biosensors have tended to have a very narrow focus.

In a bid to expand how these biosensing chips can be used, researchers from the University of California Santa Cruz (UCSC) and Brigham Young University (BYU) have developed a new testing platform that can be used for multiple types of analysis. Based on optofluidic chips – which use light to control the movement of fluids around microscale channels on a silicon or plastic chip – the new platform detects particles by illuminating them with a laser beam and then measuring the responses picked up by a light-sensitive detector. 

The research group previously demonstrated the use of this device in detecting different particle types – including nucleic acids, proteins, viruses, bacteria and biomarkers for cancer. However, these tests had always used separate detector types and signal analysis techniques depending on whether these particles were present in high or low concentrations. In their latest publication, the group reports seamless detection by fluorescence of nanobeads present in a mixture ranging eight orders of magnitude, from attomolar to nanomolar. 

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“This work is our latest step in developing integrated optofluidic sensing devices that are sensitive enough to detect single biomolecules and work over a very wide range of concentrations,” said lead study author Holger Schmidt, a distinguished professor of electrical and computer engineering and the Narinder Singh Kapany Chair of Optoelectronics at UCSC. “We have shown that this can be done with a single method, which allows us to simultaneously measure and distinguish multiple particle types at once even if they have very different concentrations.”

Improved signal processing allows for multipurpose biosensors 

In this new study, the researchers report a new signal processing method that can be used to detect particles in both high and low concentrations simultaneously, even if the concentrations present in a given sample are not known in advance. 

By combining different signal modulation frequencies for the laser – high-frequency modulation for single particles at low concentrations, and low-frequency modulation for large signals from many particles at high concentrations – the researchers can measure a much broader range of signals simultaneously.

“Secondly, we implemented a feedback loop that detects when signals are really large and adjusts the input laser power accordingly,” said Schmidt. “In this way, we can detect large signals from high concentrations without overwhelming the weak signals that may be present from another species at low concentrations. This allowed us to simultaneously detect particles that were present in very different concentrations.”

In addition, the researchers also developed a fast new algorithm that can identify single particle signals in real time. Machine learning was also applied to the signal patterns to facilitate quick recognition with high levels of accuracy. 

“These signal analysis advances are ideal for enabling device operation at the point of care where signal quality can be poor and where data analysis is required in real time,” said Schmidt.

Biosensors for medical testing

The researchers demonstrated the use of this new processing method and platform by pumping their optofluidic biosensor chips with a solution of nanobeads at differing concentrations that would fluoresce in different colors. As reported in the new paper, the researchers were able to correctly identify the concentration of both yellow–green and crimson bead concentrations in the mixture, even though their concentrations differed by a factor of more than 10,000.

“While this work advances a specific integrated sensor that is based on optical fluorescence signals, the signal analysis technique can be used with any type of time-dependent signal that covers a wide concentration range,” said Schmidt. “This can include different optical signals but also electrical sensors.”

The researchers’ technology is currently being commercialized by Fluxus Inc., a California-based medical device company. Additionally, the researchers themselves are working to adapt the method to study molecular products from artificial neuronal cell tissue organoids. Ultimately, the research project aims to provide further insight that can be applied to neurodegenerative disease and pediatric cancer research. 

Reference: Ganjalizadeh V, Hawkins A, Schmidt H. Adaptive time modulation technique for multiplexed on-chip particle detection across scales. Optica. 2023. doi: 10.1364/OPTICA.489068

This article is a rework of a press release issued by Optica. Material has been edited for length and content.