Microwave Sensors for Non-Destructive Characterization of Liquids and Biological Cells

Over the course of this thesis different types of sensors are investigated and miniaturized, aiming at the detection and characterization of individual biological cells in the microwave frequency range. Both broadband and resonant devices are studied.
The challenges towards miniaturization are manifold. For the broadband transmission-line sensors, simply decreasing the geometry is not sufficient, since the sensitivity on the sample properties decreases too strongly. Electrically small discontinuities are shown to increase the sensitivity of such sensors to some degree, but not enough to allow for downscaling to a sample volume suitable for single-cell measurements. The sensing principle is therefore changed from a transmission line measurement to the detection of a sample-dependent series capacitance. This way, the electrodes can be tapered to reduce the sample volume and the experimental results are very promising for single-cell characterization.
In case of resonant sensors, one of the main challenges is the combination of bulky resonators in the lower GHz range with small sensing tips and biocompatible materials. The proposed solution consists of a hybrid system. The microwave resonators are fabricated using materials yielding high quality factors. The sensing tips are included in a biocompatible microfabricated chip with a microfluidic channel to guide the cells into the sensing volume. The resulting sensing system is highly flexible and cost efficient, since both resonator and biocompatible chip can be easily exchanged to modify the experimental setup. For near-field sensors, the miniaturization of the sensing tips leads to a smaller impact of the sample on the resonator, reducing the sensitivity. An adapted electrode geometry with two mirror tips is used to focus the electric fields on the sample and thus increase the sensitivity even for very small samples.
Two different types of resonators are explored. Folded resonators based on waveguide cavities are used in the first designs. While they are promising with respect to sensitivity, their fabrication is quite involved due to the multi-layer setup. Additionally, only the fundamental mode can be used for sensing, because the field distribution of the higher order modes does not significantly interact with the sample. In the second design, a near-field sensor based on a coaxial transmission-line resonator is proposed. With this setup, it is possible to use several modes of the same sensor, thus allowing to probe the sample at different frequencies simultaneously. This way, the broadband permittivity can be sampled with a single resonant sensor.
Calibration procedures are proposed for both sensor types. The broadband sensing capacitance is evaluated using a suitable equivalent circuit and two calibration materials with known permittivity. The resonant sensors are calibrated using a perturbation approach which also requires two calibration materials.
The most challenging aspects of this work were of a rather practical nature. They concern the fabrication tolerances of the electrodes and the microfluidic channels, as detailed in the respective experiments. Additionally, the interface between tubing and the microfluidic channel has to be realized and sealed such that the liquid samples can be safely guided from the syringe pump to the sensing tips.
Additionally, it is clear throughout the experiments with polystyrene beads as well as with biological cells that accurate positioning is crucial for reproducible results, reflecting the material properties of the sample. Increasing the vertical distance between particles and the sensing electrodes quickly reduces the particles impact on the detected effective permittivity. The lateral position of the cells also influences the measurement results, since the electric field is strongly focused at the edges of the electrodes.
Despite the challenges and using only limited resources, some clear conclusions could be drawn. In basic research, which is the case for microwave biosensors, it is important to obtain comparable results. Different groups can validate or contradict each other only if this is given. Working towards a consistent way to interpret the measured sample properties, using, e.g., the sample permittivity, may be a good starting point towards quantifiable experimental results. The definition of a standardized measurement chamber including the electrodes and cell trap can be useful for this purpose as well.
In future research, many aspects concerning microwave sensors remain to be analyzed in more detail. To better understand the interaction between a sample and the electromagnetic fields used for sensing, further studies are required in a controlled environment. It is important to understand which biological effects cause a detectable shift of the sample permittivity to determine useful applications for microwave sensors. A system approach using integrated biochemical sensors and temperature control may allow for unambiguous measurement results. Furthermore, such a sensing system equipped with portable or even integrated electronics is a promising vision for biologically and medically relevant experiments.
Overall, the results presented in this thesis are meant as a basis for comparable experiments. Different sensor types can be compared if the interaction volume between the electric fields and the sample are similar and a suitable calibration is used. This way, microwave sensors may yet turn out to be a relevant addition to existing sensing concepts and lead to new insights in medicine and biology.