Researchers from the University of Twente have used a chip-based sensor with an integrated laser to detect low levels of a cancer protein biomarker in a urine sample. The technology is more sensitive than previous designs and could lead to noninvasive, inexpensive methods of detecting molecules that indicate the presence or progression of a disease.
The research showed that the sensor was able to perform label-free detection of S100A4, a protein associated with human tumor development, at clinically relevant levels. According to research team leader Sonia Garcia-Blanco, the technology paves the way to faster and more sensitive detection of biomarkers, which enables faster treatment and better outcomes.
Pump light coupled to the device produced lasing in a microring resonator. The surface of the resonator holds probes (red anchor molecules on the ring) that capture the analytes of interest. The laser light in the ring extends into the fluid. When analytes of interest (blue triangles) attach to the capture probes, this is sensed by the field outside the microring laser, shifting the frequency of the laser emission. This shift can be precisely measured permitting the detection of minute amounts of analytes flowing over the sensor in a 'specific' manner (i.e., the pink particles do not bind to the capture layer and are therefore not detected). In the figure, the waveguides are green (real color produced by upconversion of the dopants that induce the laser emission) and a microfluidic channel can be seen in which different particles flow from left to right. Courtesy of Rick Seubers, Optical Sciences group at the University of Twente.
The sensor detects the presence of specific molecules by illuminating the sample with an on-chip microdisk laser, made with aluminum oxide. When doped with ytterbium ions, aluminum oxide can be used to fabricate a laser that emits in a wavelength outside the light absorption band of water, while still enabling the precise detection of biomarkers. When the light interacts with the biomarker of interest, the color, or frequency, of the laser light shifts in a detectable way.
“Although sensors based on monitoring frequency shifts of lasers already exist, they often come in geometries that are not easily integrated on small, disposable photonic chips,” Garcia-Blanco said. “Aluminum oxide can easily be fabricated monolithically on chip and is compatible with standard electronic fabrication procedures.”
Using a microdisk laser rather than the nonlasing ring resonators used in other similar sensors opens the door to unprecedented sensitivity, which comes from the fact that the lasing linewidth is much narrower than the resonances of passive ring resonators. Once other noise sources, such as thermal noise, are eliminated, the method will allow the detection of minute frequency shifts from biomarkers at very low concentrations.
After developing and applying a surface treatment that captures the biomarkers of interest in complex liquids such as urine, the researchers tested the new sensor with synthetic urine containing known biomarker levels. They were able to detect S100A4 at concentrations as low as 300 picomolar.
“Detection in this concentration range shows the potential of the platform for label-free biosensing,” Garcia-Blanco said. “Furthermore, the detection module can be potentially made very simple using the developed technology, bringing it a step closer to the final application outside of the laboratory.”
The researchers are working to incorporate all the relevant optical sources and signal generation components onto the chip to make the device even simpler to operate. They also want to develop various coatings that could allow for parallel detection of a large variety of biomarkers.
The research was published in Optics Letters (www.doi.org/10.1364/OL.44.005937).