Miniaturized lab-on-a-chip for real-time chemical analysis of liquids

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Reference measurement from the Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectrometer of the thermal denaturation process of BSA, analyzed in the range of the amide I’ band between 50 ∘C (blue) and 90 ∘C ( red). The temperature-induced transition from the α-helix (1651 cm-1, blue) to the β-sheet (1615 cm-1, red) is shown. b Sensor-on-chip concept including indicated plasmonic mode. The emitter (QCL, 10 μm wide) and detector (QCD, 15 μm wide) are connected via a 48 μm long conical SiN-based plasmonic waveguide. The entire sensor is immersed in the sample solution (D2O + BSA), which is indicated by the blue transparent layer on the chip. The gold layer (plasmon waveguide and electrical contacts) is shown in gold color, the SiN passivation and dielectric filler layer are shown in brown, and the InP substrate is shown in dark gray.

Vienna University of Technology

In analytical chemistry, it is often necessary to precisely monitor the change in concentration of certain substances in liquids on a time scale of seconds. Especially in the pharmaceutical industry, these measurements must be extremely sensitive and reliable.

A new type of sensor has been developed at TU Wien which is perfectly suited for this task and combines several important advantages in a unique way: based on customized infrared technology, it is significantly more sensitive than previous standard devices. Moreover, it can be used for a wide range of molecule concentrations and it can work directly in liquid. This is the consequence of its chemical robustness and thus provides data in real time, i.e. in fractions of a second. These results have just been published in the scientific journal Nature Communications.

Different molecules absorb different wavelengths

“To measure the concentration of molecules, we use radiation in the mid-infrared spectral range,” explains Borislav Hinkov, research project leader at the Institute for Semiconductor Electronics at TU Wien. This is a well-known technique: molecules absorb specific wavelengths in the mid-infrared range, while other wavelengths are transmitted without attenuation. Thus, different molecules have their very specific “infrared fingerprint”. By accurately measuring the wavelength-dependent absorption strength profile, it is possible to determine the concentration of a particular molecule in the sample at any given time.

Infrared spectroscopy has long been used in gas detection. The new achievement of the TU Wien team is the implementation of this technology on a finger-sized sensor chip, which is specifically suited for liquid detection. The development of such a sensor was a technological as well as an analytical challenge, since liquids absorb infrared radiation much more strongly than gases. The compact liquid sensor was realized in collaboration with Benedikt Schwarz from the Institute of Solid State Electronics and manufactured at the Center for Micro- and Nanostructures, the state-of-the-art clean room at TU Wien.

“We only need a few microliters of liquid for one measurement,” explains Borislav Hinkov. “And the sensor provides data in real time, multiple times per second. Thus, we can accurately track a concentration change in real time and measure the current state of a chemical reaction in the beaker. This is in stark contrast to other benchmark technologies, where you have to take a sample, analyze it, and wait up to a few minutes for the result.

Collaboration between different disciplines is key

This was made possible through a collaboration between the departments of Electrical Engineering and Chemistry of TU Wien: The Institute of Semiconductor Electronics has extensive experience in the design and manufacture of lasers and cascade detectors quantum. They are tiny semiconductor-based devices that can emit or detect infrared laser radiation with a precisely defined wavelength based on their micro and nanostructure.

The infrared radiation emitted by such a laser penetrates the liquid at the micrometer scale and is then measured by the detector on the same chip. Using these specially combined ultra-compact lasers and detectors, a detection device was realized and its performance was tested in the first proof-of-concept measurements. The work was carried out in collaboration with the group of Bernhard Lendl from the Institute for Chemical Technologies and Analytics.

Experimental demonstration: a protein changes structure

To demonstrate the performance of the new mid-infrared sensor, a reaction from biochemistry was selected: a known model protein was heated, thus modifying its geometric structure. Initially, the protein has the shape of a helix-like coil, but at higher temperatures it unfolds into a flat structure. This geometric change also alters the particular mid-infrared fingerprint absorption spectrum of the protein. “We selected two suitable wavelengths and fabricated suitable quantum cascade sensors, which we integrated on a single chip,” explains Borislav Hinkov. “And indeed, it turns out that you can use this sensor to observe the so-called denaturation of the selected model protein with high sensitivity and in real time.”

The technology is extremely flexible. It is possible to adjust the necessary wavelengths as needed to study different molecules. It is also possible to add other quantum cascade sensors on the same chip to measure different wavelengths and thus simultaneously distinguish the concentration of different molecules. “This opens up a new field in analytical chemistry: real-time mid-infrared spectroscopy of liquids,” says Borislav Hinkov. The possible applications are extremely diverse – they range from the observation of thermally induced structural changes in proteins and similar structural changes in other molecules, to the real-time analysis of chemical reactions, for example in the production of pharmaceutical drugs. or in industrial manufacturing processes. Wherever it is necessary to monitor the dynamics of chemical reactions in liquids, this new technique can bring significant benefits.

The work was funded by a Lise-Meitner grant from the FWF to Borislav Hinkov and by the EU Horizon2020 project “cFlow”.

A mid-infrared lab-on-a-chip for dynamic reaction monitoring, Nature Communications

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