Das Institut

Silicon-based chemical sensors and biosensors, in terms of their micro- and nano-technological aspects, represent a challenging interdisciplinary area with a high potential for innovation. The importance of this topic is defined by the demand for miniaturization on the one hand, and the integration of sensors, actuators, and mechanical or fluidic elements onto one sensor chip and thus, the creation of miniaturized multifunctional analytical systems such as “lab-on-a-chip”, electronic tongue devices, µTAS (micro total analysis systems) or MEMS (micro-electro-mechanical system), on the other.To develop these sensor systems, a high standard of resources in both silicon- and thin-film processing is necessary, along with facilities to establish the characterization of micro- and nanostructures, especially at their interfaces and surfaces. In addition, tools for simulation and modeling in several dimensions are gaining importance in the development of micro- and nanosensors.

Besides fundamental research issues, chemo- and biosensorics together with chip technologies increasingly include application-oriented subjects. Here, the combination of micro- and nanostructures with stimulating functional materials offers a high potential for the development of intelligent sensor/actuator systems for numerous applications.

Research activities for medium- and long-term development include the following:

• Sensors and sensor systems including intelligent signal processing for (bio-)chemical parameters based on field-effect devices and microelectrodes for the determination of ions and metabolic products in application fields such as biomedicine, food analysis, process technology and environmental monitoring.
• Advanced fabrication technologies for micro- and nanostructured semiconductor-based sensor systems and utilization of functional intelligent materials for developing both micro- and nanosensors and actuators.
• Bioelectronic and biophysical sensors, gas sensors.
• Basic research studies concerning the functionalized “solid/liquid” interface and “solid/biomolecule” hybrid system for the characterization of micro- and nanoaspects of sensor devices.

We develop and evaluate novel enzymes with the aim of direct technical application. One part of our approach is the efficient production of highly pure chiral compounds. Currently, the research is focused on the following topics:

• Evaluation and use of novel enzymes for different technical applications, e.g. biosensor development. One example is the development of a diacetyl and acetoin sensor for the monitoring of fermentation processes and evaluation of acetoin reductases/butanediol dehydrogenases in biotransformations (in cooperation with J. Bongaerts, T. Selmer, T. Wagner, M.J. Schöning).

Diacetyl and acetoin exhibit a butter-like flavor in alcoholic beverages, like beer and wine. These compounds are undesired in beers to give a clean, crisp taste, whereas higher concentrations of these compounds are desired in wines for a smoother taste and feel. Different novel acetoin reductases are recombinantly produced and investigated for the quantitative determination of diacetyl and acetoin in microbial fermentations.
Vicinal diketones, like diacetyl, are not only naturally produced in fermentation processes but can also yield chiral α-hydroxy ketones and vicinal diols by stepwise reduction. These are interesting synthons for complex chiral structures or monomers for mixed polymers with unique properties, respectively. As the chemical synthesis of enantiomerically pure α-hydroxy ketones or vicinal diols is difficult to achieve the direct, biocatalytic conversion of vicinal diketones with enzymes is advisable. Selected acetoin reductases/butanediol dehydrogenases are developed to achieve that aim.

• Influence of enzymatic substrate pre-treatments on biogas production (together with the NOWUM Energy Institute, I. Kuperjans).
• Development of technical enzymes, e.g. subtilisins (in cooperation with J. Bongaerts).

Subtilisin protases are widely used in different industries, e.g. as an active component in laundry detergents. In this work, we aim to find even more suitable novel enzymes by cloning of new genes with relatively low homology to already known subtilisin genes and evaluation of the biochemical and performance parameters of the subsequent enzyme

Magnetic field sensing is a particularly valuable measurement technique for biomedical applications because of its non-invasive nature. In the Magnetic Field Sensors lab on the campus of Forschungszentrum Jülich, various magnetometers and their readout electronics are being developed. The research activities include the characterization of the sensors regarding their transfer characteristics and noise performance, and the development of applications in magnetic biosensing. Superconducting Quantum Interference Device (SQUID) systems with liquid nitrogen cooling have been developed and successfully applied to adult and fetal magnetocardiography.

Magnetic nanoparticles (MNP) are particularly attractive for biochemistry because of their double function as handle and marker. They are used for concentration enhancement or separation by pulling them with a magnetic gradient field, and they are magnetically detected and quantified by means of frequency mixing magnetic detection (FMMD). This technique is based on the specific detection of intermodulation products upon two-frequency magnetic excitation which are generated due to the nonlinear magnetization characteristics of the superparamagnetic particles. As these sum frequency components are not present without the magnetically nonlinear particles, the method exhibits a particularly high selectivity for magnetic nanoparticles with a large dynamic range. The marker functionality is used in magnetic immunoassays, which employ the highly specific interaction between antigenes and antibodies for the detection and quantification of biomolecules bound to MNP markers. Together with Fraunhofer IME Aachen, we develop magnetic immunoassays, for instance against viruses, proteins, bacteria, toxins and antibodies, in different matrices such as blood, urine, saliva, or plant extracts. The magnetic assays usually exhibit a better sensitivity and need less time than conventional assays such as ELISA.

In cooperation with research partners in China and South Korea, research on Low Field (LF) Nuclear Magnetic Resonance (NMR), Magnetic Resonance Imaging (MRI), and Magnetic Particle Imaging (MPI) is being conducted. Based on strong rare earth magnets in Halbach configuration, the development of open and mobile low-cost systems with significantly less complexity than standard MRI becomes feasible. LF-MRI exhibits the explicit benefit that tissue contrast is particularly pronounced at low fields. Biocompatible iron oxide MNP can be used as markers functionalized with antibodies, or for contrast enhancement. MPI allows to image their distribution in 3D. Together with ETRI, Korea, an MPI imaging system based on FMMD detection is under development.

The laboratory for optical micro- and nanosystem technology combines different light-addressable technologies to create new types of sensors and actuators. On the sensor side, the main focus is on the light-addressable potentiometric sensor (LAPS), whereby changes in ion concentration and biomolecules could be determined on the sensor surface. Furthermore, light-responsive hydrogels are investigated, namely in terms of shrinking and swelling behavior. As a possible application this behaviour could be used in microfluidic channels as valves to control liquid flow streams.

Another field of interest is the light-addressability of living cells, using a light source to switch on or off certain metabolic pathways of cells. Also, light-addressable electrodes will be investigated to e.g., trigger catalytic processes in liquids such as the change of the pH value of the analyte.

Finally, the different areas of this research should be combined into a single system, comprising microfluidic channels, light-addressable cells and hydrogels as well as light-addressable electrodes and sensors. Such a system could be used to help current research investigations in medicine, pharmacy as well as basic research.

To support these set-ups, 3D-printing techniques are utilized to realize fast development and prototypes of new measurement set-ups, including microfluidics, configurations for measurement cells etc.

Over the past few years, the significance of Cell Culture Technology has increased considerably. It has become a key technology for the production of therapeutical proteins using biotechnology. Only mammalian cells can synthesize complex glycosylated proteins in an efficient manner. The expression of such proteins is industrially performed using recombinant hamster cells (CHO) or mouse cells (hybridomacells). For large-scale fermentation, suspension cultures in stirred tank fermenters are used in a scale up to 100 m3. The most relevant process technology is the fed-batch culture, using controlled feeding of the culture with media concentrates to prevent nutrient limitations.

Recent methods for process optimization are aimed at reducing the time of process development. For this purpose, fermentation data must be obtained even in the early stages of fermentation under controlled and reproducible conditions in order to allow a scale up of the process later on.

According to this, the research and development activities of the “Laboratory for Cell Culture Technology” are application-oriented and aimed at the development of:

• Parallel and miniaturized culture systems for mammalian cells.
• Methods for obtaining relevant culture data for optimisation of the media composition and the culture process.
• Measuring and balancing metabolic effects (e.g., OTR, CTR) and using them for process control.
• Development of methods for on-line analysis of metabolite concentrations.
• Offering practical (training) courses for cell culture fermentation.

Surgery, radiotherapy and chemotherapy are the standard therapies for local tumor treatment and results commonly in a significant loss of quality of life and, moreover, in many cases effectiveness is limited. For example, in the case of prostate cancer, about one-third of patients will develop progressive or metastatic disease within 10 years after conventional treatment [Oefelein, M.G. et al., J Urol 158 (1997) 1460-1465]. In early metastatic disease androgen ablation is effective, but in most cases androgen-independent tumors develop. Subsequently, no effective treatment for androgen-independent prostate disease is available. 
A promising possibility to render a therapeutic cancer treatment more effective could be the development of cancer-specific vaccines. The idea behind this approach is to activate the body's own defense system (especially, cytotoxic T lymphocytes) against cancer cells.

The activities of our laboratory “Applied Immunology” are focussing on the development and preclinical characterization of new therapeutic vaccines against cervical and prostate cancer.

Currently, the research is addressing on the following projects:

• Development of a multivalent therapeutic HPV-16 and HPV-18 -specific DNA vaccine against cervical cancer
• Development of a plant expressed therapeutic vaccine against cervical cancer
• Development of a prostate cancer DNA vaccine

Microorganisms, such as bacteria, archaea and fungi, are divers and exhibit remarkable metabolic variability. This makes microorganisms even more interesting as production organisms for valuable products. Since renewable raw materials are converted, they will make a decisive contribution to a sustainable economy, also referred to as bioeconomy. Industrial microbiology deals with the identification, evaluation, improvement and utilization of microorganisms in order to produce a wide range of products, including foods, beverages, platform chemicals, fuels, pharmaceuticals and enzymes. Bacillus species, mainly B. subtilis, B. licheniformis and B. amyloliquefaciens, are well-established production hosts for important technical enzymes on a very large scale. Nevertheless, it is important to identify and develop new production hosts to improve the availability of industrial enzymes, both novel and existent, in competitive yields and to open the process for new potential. On the other hand, genetic accessibility of already established production strains is often very limited. This leads to the need for better tools, in particular when the aim is to engineer the genome.

Currently, the research is focused on the following projects:

• Evaluation of several Bacillus species as alternative hosts for the production of technical enzymes.
• Development of new methods for targeted chromosomal engineering of different Bacillus species.
• Fermentation process development, including  biosensor development.