Microfluidic Active-Feedback THz Biosensor for Direct, Sensitive and Selective Exosome and Virus Detection in Aqueous Environments (“MATISSE”) 

Emerging around the year 2000, THz bioanalytic techniques have become a strongly growing field of research, since many biomolecules and biomolecular complexes show a rich and relevant intra- as well as intermolecular resonance spectrum in the THz regime [1-3].

The MATISSE project aims beyond individual biomolecular detection, towards the THz analysis and detection of more complex entities and complexes at the root of intercellular signaling and disease propagation: vesicular structures. Vesicles are found inside the cell transporting contents to the outside but also extracellularly as so-called exosomes. These exosomes are cell-to-cell transit systems in the human body with pleiotropic functions in the focus of recent research interest (cf. [4]). Exosomes are excellent non-hazardous model systems for potentially dangerous viruses, that also belong to the group of vesicles, like e.g. SARS-CoV2.

All these small biological structures (viruses, exosomes) carry and present marker molecules on their surface, by which specific detection is possible. However, detection is still time consuming, requiring advanced biomedical techniques and appropriately trained professionals. To exemplify this using the current problem of SARS-CoV2: Highly specific and sensitive detection is currently only possible by an indirect, time consuming technique, the detection of viral RNA after reverse transcription and amplification by PCR (polymerase chain reaction). Faster tests focus of the detection of a viral protein; however, these are known to be less sensitive and specific.

In the MATISSE project, a microfluidic THz biochip with integrated active electronic read-out will be developed for the fast and reliable detection of exosomes and virus particles with high specificity. Our distant aim is that body fluids, potentially carrying virus particles, will pass through the microfluidic THz biosensor and said virus particles are kept by an antibody against structures on their surface (e.g., the Spike protein in the case of SARS-CoV2). After accumulation of potentially present particles, these are detected via THz technology. Sufficient positive and negative controls will make a selective distinction and quantification possible, apart from simple yes/no answers.

The project is part of the DFG (German Research Foundation) founded SPP 2314 INTEREST (INtegrated TERahErtz sySTems enabling novel functionality). Further information is available on the project website .

Figure 1: Graphic representation of analytes ad­dres­sed in this project. a) liposomes and exosomes are deposited on the sensor surface unspecifically; b) exosomes naturally presenting different proteins in the bilipid membrane. Only matching exosomes adhere to on the sensor surface immobilized antibodies, non­matching exosomes are washed off; c) modified exosomes presenting virus protein bind to the same antibody as the virus itself.

[1] A. Markelz, et al., “Pulsed terahertz spectroscopy of DNA, bovine serum albumin and collagen between 0.1 and 2.0 THz,” Chem. Phys. Lett. 320, pp. 42–48, 2000.

[2] M. Walther, et al., “Far-infrared vibrational spectra of all-trans, 9-cis and 13-cis retinal measured by THz time-domain spectroscopy,” Chem. Phys. Lett. 332, pp. 389–395, 2000.

[3] R. J. Falconer et al., “Terahertz Spectroscopic Analysis of Peptides and Proteins,” J Infrared Milli Terahz Waves 33, pp. 973–988, 2012.

[4] R. Kalluri et al., “The biology, function, and biomedical applications of exosomes,” Science 367, 2020.