Bioanalytical THz sensing techniques have proven to be an interesting and viable tool for the label-free detection and analysis of biomolecules. However, a major challenge for THz bioanalytics is to perform investigations in the native aqueous environments of the analytes. This review recapitulates the status and future requirements for establishing THz biosensing as a complementary toolbox in the repertoire of standard bioanalytic methods. The potential use in medical research and clinical diagnosis is discussed. Under these considerations, this article presents a comprehensive categorization of biochemically relevant analytes that have been investigated by THz sensing techniques in aqueous media. The detectable concentration levels of ions, carbohydrates, (poly-)nucleotides, active agents, proteins and different biomacromolecules from THz experiments are compared to characteristic physiological concentrations and lower detection limits of state-of-the-art bioanalytical methods. Finally, recent experimental developments and achievements are discussed, which potentially pave the way for THz analysis of biomolecules under clinically relevant conditions.

Metamaterials can be utilized for a variety of applications and have emerged as a valuable tool in THz technologies. Used as THz biosensors, metasurfaces can significantly improve the sensitivity in the detection of biomolecules, but the high THz absorption of water represents a major challenge for the realization of a sensor for measurements in liquids. In this article, we propose an approach where the resonance feature of complementary asymmetric split ring resonators (CASRR) is maintained even for measurements in water, allowing highly sensitive detection of biomolecules in strongly absorbing liquids. This is enabled by the introduction of substrate-integrated microfluidics, which are shown to have a minimal effect on the transmission properties of the metamaterial. Due to this approach, the metamaterial structure design is independent from the microfluidic channels. Our simulations also show that the sensitivity of CASRR changes only marginally for lossless and highly absorbing materials. At the same time, the presented concept is easy to fabricate by standard lithography methods and can be applied to other metamaterial structures as well.

Due to the occurrence of THz-excited vibrational modes in biomacromolecules, the THz frequency range has been identified as particularly suitable for developing and applying new bioanalytical methods. We present a scalable THz metamaterial-based biosensor being utilized for the multifrequency investigation of single- and double-stranded DNA (ssDNA and dsDNA) samples. It is demonstrated that the metamaterial resonance frequency shift by the DNA’s presence depends on frequency. Our experiments with the scalable THz biosensors demonstrate a major change in the degree of the power function for dsDNA by 1.53 ± 0.06 and, in comparison, 0.34 ± 0.11 for ssDNA as a function of metamaterial resonance frequency. Thus, there is a significant advantage for dsDNA detection that can be used for increased sensitivity of biomolecular detection at higher frequencies. This work represents a first step for application-specific biosensors with potential advantages in sensitivity, specificity, and robustness.

Terahertz (THz) biosensing has emerged as an important research field, mainly driven by the resonant behavior of many biomolecules in this spectral range which holds potential for highly sensitive analyses. In this work, we present a detailed overview of our current research on THz biosensing, focusing on the development and analysis of THz biosensors based on frequency selective surfaces (FSS) for two different measurement scenarios: i) label-free, highly sensitive and selective analysis of dried biomolecules, and ii) sensitive and selective analysis in an aqueous environment. With our carefully designed THz biosensor for measurements in the dry state, we were able to indirectly measure tumor-marker MIA RNA in a concentration as low as 1.55 × 10−12 mol/L, without the need for biochemical amplification. Our biosensor with substrate-integrated microfluidics for terahertz measurements in an aqueous environment is validated by simulations, showing that the resonance feature in the frequency response of our sensor is maintained even for measurements in water.

No abstract