Advancements in Medical Diagnostics: All-Purpose Biosensor Chip with an Extended Detection Range of 10,000-Fold

Caption: A breakthrough in signal-processing techniques coupled with an optofluidic biosensor chip allows for the detection of nanobead mixtures spanning a vast range of concentrations. Image credit: Holger Schmidt, ECE Department, University of California, Santa Cruz

Scientists from UC Santa Cruz have made significant strides in enhancing chip-based biosensors, revolutionizing the detection range by over 10,000 times. This breakthrough empowers a single device to simultaneously conduct multiple medical tests on diverse biomolecules, even when their concentrations greatly vary. By incorporating machine learning for precise particle recognition, these biosensors become ideal for real-time data analysis in point-of-care scenarios.

The research team has achieved remarkable advancements in chip-based sensing devices designed for substance detection and analysis. These developments pave the way for highly sensitive, portable, integrated optofluidic sensing devices capable of performing a multitude of medical tests concurrently, regardless of the vastly different concentrations of bioparticles involved, such as viral particles and DNA.

In a study published in Optica, the high-impact research journal of Optica Publishing Group, Holger Schmidt, leading the research team from the W.M. Keck Center for Nanoscale Optofluidics at the University of California, Santa Cruz (UCSC), employed novel signal-processing techniques on an optofluidic chip-based biosensor. These techniques enabled seamless fluorescence detection of a mixture of nanobeads spanning concentrations across eight orders of magnitude, ranging from attomolar to nanomolar. Consequently, the concentration range in which these sensors can operate has been extended by a factor of more than 10,000.

Schmidt remarked, “This work represents our latest advancement in the development of integrated optofluidic sensing devices that possess the sensitivity to detect single biomolecules and operate effectively over an extensive concentration range. We have demonstrated that this can be achieved using a single method, allowing us to simultaneously measure and differentiate multiple particle types, even when they possess significantly different concentrations.”

To detect molecules at both high and low concentrations concurrently, the researchers introduced distinct signal modulation frequencies. They utilized high-frequency laser modulation to differentiate single particles in low concentrations, while low-frequency laser modulation detected substantial signals from numerous particles at high concentrations. The accompanying image displays the optical setup and the custom-developed control software in operation. Image credit: Holger Schmidt, ECE Department, University of California, Santa Cruz

Creating a Versatile Testing Device

While several chip-based testing devices have been developed, most are tailored to a specific target or type of test due to the wide variety of biomolecules that exist in varying quantities. For instance, concentrations of different proteins used as disease biomarkers can vary by over ten orders of magnitude.

Schmidt’s group, in collaboration with Aaron Hawkins at Brigham Young University, endeavors to develop a testing platform suitable for multiple types of analyses. Their platform is based on optofluidic chips, which integrate optics and microfluidic channels on a silicon or plastic chip. Particles are illuminated with a laser beam and their response is measured using a light-sensitive detector for detection.

Previously, the researchers demonstrated that their platform possesses the required sensitivity to conduct various types of analyses and can detect numerous particle types, including nucleic acids, proteins, viruses, bacteria, and cancer biomarkers. However, until now, separate detectors and signal analysis techniques were necessary to measure particles with high and low concentrations. This was due to the fact that if one particle type is present in very high concentrations, it generates a significantly larger response that overwhelms the much weaker signals from another particle type present in low concentrations.

Enhanced Signal Processing

In their recent work, Schmidt and graduate student Vahid Ganjalizadeh developed signal processing methods capable of simultaneously detecting particles at high and low concentrations, even without prior knowledge of the concentrations. They achieved this by combining different signal modulation frequencies: high-frequency laser modulation to differentiate single particles at low concentrations and low-frequency laser modulation to detect substantial signals from multiple particles simultaneously at high concentrations.

Schmidt explained, “Furthermore, we implemented a feedback loop that detects excessively large signals and adjusts the input laser power accordingly. This enables the detection of significant signals from high concentrations without overwhelming the weak signals that may be present from another species at low concentrations. Consequently, we can simultaneously detect particles present at significantly different concentrations.”

The researchers also applied an exceptionally fast algorithm they recently developed to identify single-particle signals at low concentrations in real-time. Machine learning aided in recognizing signal patterns, enabling accurate differentiation of various particle types. Schmidt added, “These advancements in signal analysis are particularly valuable for facilitating device operation at the point of care, where signal quality can be poor and real-time data analysis is necessary.”

Distinguishing Low and High Concentrations

The researchers validated their new signal analysis approach by introducing a solution of nanobeads with varying concentrations and fluorescence colors into optofluidic biosensor chips. Remarkably, they accurately identified both yellow-green and crimson bead concentrations, even when their concentrations differed by a factor of more than 10,000 within the mixture.

“While this work advances a specific integrated sensor based on optical fluorescence signals, the signal analysis technique can be applied to any type of time-dependent signal that covers a wide concentration range,” highlighted Schmidt. “This includes different optical signals as well as electrical sensors.”

Fluxus Inc., a medical device company, is currently commercializing the team’s optofluidic biosensing technology. Additionally, the researchers are working on adapting their methods to study molecular products from artificial neuronal cell tissue organoids. This project, a part of the UCSC Center for Live Cell Genomics, an NIH Center for Excellence in Genomic Science, could offer valuable insights into areas such as neurodegenerative diseases and pediatric cancer.

Reference: “Adaptive time modulation technique for multiplexed on-chip particle detection across scales” by V. Ganjalizadeh, A. R. Hawkins, H. Schmidt, 22 June 2023, Optica. DOI: 10.1364/OPTICA.489068

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More about biosensor technology

• Optica – Adaptive time modulation technique for multiplexed on-chip particle detection across scales
• University of California, Santa Cruz – Press Release
• Fluxus Inc. – Official Website