@PhdThesis{duepublico_mods_00042380,
  author = 	{Mross, Stefan},
  title = 	{Integrated Multi-Sensor System for Parallel In-Situ Monitoring of Biotechnological Processes},
  year = 	{2016},
  month = 	{Oct},
  day = 	{28},
  abstract = 	{Due to increasing complexity of bioprocesses in production and research, e.g. in the fabrication of antibodies and vaccines, and high efficiency and product safety requirements, precise monitoring and control in biotechnology becomes increasingly important. In this work a multi-sensor system for the parallel in-situ monitoring of the four important process parameters glucose, lactate, cell density and pH in bioprocesses is developed.
The fabrication process of the sensor chip, based on a CMOS process flow, is suitable for integration into standard processes and mass production of the system. Thanks to the continuous, parallel measurement directly inside the bioreactor the system is considerably simpler, smaller, more cost-effective and easier to sterilize than the state-of-the-art measurement approach, which involves a separate sensor for every parameter and sampling and external measurement for glucose and lactate.
The focus of this thesis is on the development of amperometric enzyme sensors for glucose and lactate that cover the wide concentration ranges found in bioprocesses. These range from a few millimoles per liter (mM) to concentrations above 1000 mM. To achieve such wide measurement ranges diffusion-limiting membranes
are employed. Two membrane materials, poly(dimethylsiloxane) (PDMS) and polyurethane (PU), are assessed for this purpose, examining the surface morphology, permeability and long-term performance of fabricated membranes. Using PDMS membranes glucose is measured up to 200 mM, and with sensors covered with PU membranes concentrations up to 600 mM glucose and 900 mM lactate are measured. These ranges include a significant part of the concentrations found in bioprocesses. The glucose sensors are employed in long-term measurements and show good performance in the continuous monitoring of a yeast culture over 13 days and weekly calibration measurements over 30 days.
The cell density sensor is realized as interdigitated platinum electrodes, and cell density is determined via conductivity changes of a cell suspension. Measurements are performed up to 20 g/l dry cell weight, covering a significant part of the cell densities found in bioprocesses.
The pH is determined in C-V measurements via threshold voltage shifts at an electrolyte-insulator-semiconductor structure. Ta2O5 is employed as a pH-sensitive material, deposited on the chip surface by an atomic layer deposition (ALD) process. The sensor is able to measure pH in a range from pH 3 to pH 12, being suitable for any medium used in cell cultures. Both sensors show good performance and tight correlation with reference measurements when used in the monitoring of yeast culture.
The glucose and cell density sensor in parallel are successfully employed in the monitoring of a yeast culture, showing good correlation with reference measurements. The feasibility of the parallel operation of multiple sensors on one chip is proven, and the advantage of the multi-sensor system in comparison to single sensors is demonstrated.},
  url = 	{https://duepublico2.uni-due.de/receive/duepublico_mods_00042380},
  file = 	{:https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00042325/Mross_Diss.pdf:PDF},
  language = 	{en}
}