Volume 76, Issue 11-12 - Special Issue: Electromagnetic Sensors for Life Sciences; Guest Editors: Anja Bosserhoff, Christian Damm and Ulrich Göringer

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.

Localized Surface Plasmon Resonances (LSPR) based on highly doped semiconductors microstructures, such as antennas, can be engineered to exhibit resonant features at THz frequencies. In this work, we demonstrate plasmonic antennas with increased quality factor LSPRs from Fano coupling to dark modes. We also discuss the advances in the biofunctionalization of n-doped Ge antennas for specific protein immobilization and cell interfacing. Finally, albumin biolayers with a thickness of a few hundred nanometers are used to demonstrate the performance of the fano-coupled n-Ge antennas as sensors. A resonant change of over 10% in transmission, due to the presence of the biolayer, can be detected within a bandwidth of only 20  GHz.

Human African Trypanosomiasis (HAT) is caused by the African trypanosome, a single-cell parasite that proliferates in the blood and cerebrospinal fluid of infected patients. Diagnostic measures for this pathogen are currently not sufficiently robust and reliable enough to permit effective disease control procedures. As a consequence, we suggested the development of a new sensor type, combining the selectivity of parasite-specific nucleic acid aptamers with the sensitivity of resonant electromagnetic devices to capture and detect the disease-causing organism. While we accomplished the detection of parasite cells in dehydrated specimens, here we summarize our recent progress toward electromagnetic sensors capable of uncovering parasites in liquid patient samples. We present a technique for the removal of blood cells from blood specimens and the deposition of trypanosome cells on glass microfiber membranes for dielectric spectrometry. Liquid suspensions of trypanosomes are characterized to determine the actual dielectric properties of single parasites and lastly, we present two sensor concepts optimized for the detection in liquids, along with a fabrication technique for the integration of microfluidic sample confinements.

Diagnostic applications for skin in the microwave range have developed significantly in recent years, due the non-invasiveness of these applications and their ability to assess tissue water content. Despite their capabilities, however, there is still no appropriate clinically applicable microwave tool for the assessment of burn wounds. A common practice is the visual inspection and evaluation of burns by the doctor, which is a challenging task even for experienced medical professionals. An incorrect assessment can have far-reaching consequences, such as unnecessary surgery or surgery that is necessary but omitted. In this paper, two different approaches of millimeter-wave burn wound assessment are presented: millimeter-wave imaging and near-field spectroscopy. For imaging, a MIMO sparse array was used to assess ex vivo burns on porcine skin in the frequency range of 70–80 GHz. With a resonant millimeter-wave near-field probe, reflective spectroscopy at individual sites of an ex vivo burn on porcine skin in the frequency range of 75–110 GHz was performed. The results showed individual advantages and drawbacks for both approaches, with surprising benefits of the spectroscopic method. Nevertheless, both approaches were shown to be suitable for clinical usage in diagnosing burns.

We demonstrate a full-cycle breath gas sensor system based on terahertz/millimeter-wave gas spectroscopy. The sensor consists of a transmitter and receiver working around 250 GHz based on SiGe BiCMOS technology. Typical detection thresholds are in the ppm range depending on the respective molecule. The data analysis provides partial pressures of the investigated molecules by fitting of spectra which are measured by wavelength modulation. Beside the spectroscopic measurement and the data analysis, a full cycle of breath analysis includes the sampling and the conditioning of the sample tubes. The full cycle takes about 35 min per sample in average. As the system is compact and easy to operate, it allows for on-site analysis of breath samples in medical laboratories or hospitals.

The purpose of this work is to further develop a novel dual-mode microwave applicator for diagnosis and thermal ablation treatment. The MR-compatible MW applicator enables differentiation of tumor tissue and healthy tissue through dielectric contrast measurements, optimizing the positioning of the applicator in the lesion. Due to the robust applicator design and the resulting permittivity tracking during ablation, even carbonized tissue can be detected. The use of operating frequencies between 5 and 10 GHz allow a noticeably lower power consumption for microwave ablation of only 20 W compared to commercially available applicators. Clinically relevant dimensions of ablation zones can be achieved and additionally monitored using MR imaging and thermometry.

Dielectric spectroscopy in the sub-THz regime is a promising candidate for microfluidic-based analysis of biological cells and bio-molecules, since multiple vibrational and rotational transition energy levels exist in this frequency range (P. Siegel, “Terahertz technology in biology and medicine,” IEEE Trans. Microw. Theor. Tech. , vol. 52, pp. 2438–2447, 2004). This article presents our recent efforts in the implementation of microfluidic channel networks with silicon-based technologies to unleash the potential of an integrated sub-THz microfluidic sensor platform. Various aspects of dielectric sensors, readout systems, flowmeter design as well as implemention- and technology-related questions are addressed. Three dielectric sensor systems are presented operating at 240 GHz realizing transmission-based, reflection-based and full two-port architectures. Furthermore different silicon based microchannel integration techniques are discussed as well as a novel copper pillar-based PCB microchannel method is proposed and successfully demonstrated.

Electron paramagnetic resonance (EPR) is the gold standard for studying paramagnetic species. As an example, in structural biology, it allows to extract information about distance distributions on the nanometer scale via site-directed spin labeling. Conventional pulsed EPR of biological samples is currently limited to relatively large sample concentrations and cryogenic temperatures, mainly due to low sensitivity and the significant dead time associated with conventional resonator-based EPR setups, essentially precluding in-cell EPR under physiological conditions. This paper presents our latest progress toward single-cell pulsed EPR using VCO-based EPR-on-a-chip (EPRoC) sensors. Together with an analytical model for VCO-based pulsed EPR, we present an experimental scheme to perform dead-time-free pulsed EPR measurements using EPRoC detectors. The proposed scheme is validated using extensive numerical simulations and proof-of-concept experiments on the spin dynamics of an organic radical at room temperature using a custom-designed EPRoC detector operating in the Ka-band around 30.4 GHz. Additionally, we discuss methods to improve the excitation field homogeneity and sample handling through chip post-processing and custom-designed microfluidics. Finally, we present our progress towards compact, portable pulsed EPR spectrometers incorporating EPRoC detectors, microfluidics, and custom-designed permanent magnets. Such portable EPR spectrometers can pave the way toward new EPR applications, including point-of-care diagnostics.

We demonstrate operation of a micropore based flow cytometer in the radio-frequency range. Apart from simply counting micron sized particles, such as cells, with close to nano-second resolution this counter offers the additional benefit of delivering insight into the intracellular environment. Such non-invasive screening of the cell’s interior based on analysing amplitude and phase of the signal is helpful in characterizing the biological activity of cells. In detail we are using heterodyne mixing to demodulate the temporal impedance changes, which are induced by cells translocating through a micropore embedded in a radio-frequency circuit. This allows us to measure every amplitude and phase modulation induced by a translocation event. Herein, we compare the Jurkat cells (human T lymphocytes) recordings with a control group of polystyrene beads. As the cells are measured on a single cell level, the variations on the measured amplitude and phase signals are used, herein, to sense morphological cell changes in real time.

The advancement of micro and nanotechnology has led to the manufacturing of miniaturized sensors with improved functionalities for highly sensitive point of care devices. This work is particularly focused on analysing cancer cells and the effect of a model drug on their survival rate. To that end, we developed a highly sensitive rolled-up micro-electrochemical impedance spectroscopy sensor, encapsulated into a microfluidic channel. The sensor was built by strain engineering of shapeable materials and with diameters close to the cell size to improve their sensitivity. To demonstrate the platform performance, we first carried out measurements with different electrode geometries using cell medium at different concentrations. We also performed measurements using cancer cell suspensions, obtaining distinct signals from single cells, cell clusters and cellular debris. Finally, cancer cells were treated with an anticancer drug (Camptothecin), at different concentrations, over the same period, and further analysed using the developed platform.