Integrated multi-sensor system for parallel in-situ monitoring of cell nutrients, metabolites, cell density and pH in biotechnological processes

Abstract

We report on a multi-sensor system for the parallel in-situ monitoring of cell nutrients, metabolites, cell density and pH in biotechnological processes. 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. The integration of enzyme sensors for wide concentration ranges, an impedance-based sensor and a pH sensor on one silicon chip for in-situ applications in bioreactors, fabricated in a CMOS-based process flow, is demonstrated for the first time to our best knowledge. Measurements of glucose and lactate concentrations in a wide range are shown with linear ranges up to 600mM and 900mM, respectively. Cell density is determined via conductivity changes of a cell suspension and measurements are performed up to 15g/l dry cell weight. The pH sensor is based on C-V measurements at an electrolyte-insulator-semiconductor structure and able to measure pH in a range from pH 3 to pH 12. All sensors are successfully employed in the monitoring of cultures of Saccharomyces cerevisiae or Lactobacillus acidophilus.