Construction of electrochemical transducers with recessed microelectrode arrays for biomedical applications using CMOS processes.

摘要

New ideas in science and technology have always been created at the interface of different subjects. For instance, the rapid progress of micro-systems and nanotechnology gave tremendous impulses to “classical” chemical sciences like analytical chemistry, electrochemistry, polymer chemistry, as well as biochemistry, medicine and biology. Biomedical sensors are among the first generation of biochips, the combination of biological material with technical transducers.; Photolithographic processes, commonly used for the fabrication of microelectronics, allow the precise manufacture and mass-production of electrochemical systems with novel features for biomedical applications. The aim of this thesis is the fabrication of novel miniaturized microelectrode systems with CMOS compatible processes and their subsequent characterization as well as their applications for amperometric biomedical sensors. The potential of recessed microelectrode arrays that were constructed to serve as working electrodes is investigated. It is found that the produced electrodes have a very high current density, are less influenced by flow perturbations and enable flow-through measurements with small analyte volumes. The electrode systems constructed featured multiple working electrodes to allow for detection of different analytes simultaneouly. As applications, a dissolved oxygen sensor, and a lactate/glucose flow-injection biosensor were constructed as a micro total analysis system (μ-TAS) predecessor.; The presented work can be subdivided into two parts: Firstly, electrode chips consisting of two platinum working microelectrode arrays, a silver/silver chloride reference electrode and a platinum auxiliary electrode were designed, produced, characterized and used for dissolved oxygen measurements. Arrays of twelve different dimensions were manufactured to study the influence on their electrochemical behaviour and to find the optimal values. Secondly, based on the previous findings an advanced electrode systems containing four working microelectrode arrays, a silver/silver chloride reference electrode, a platinum auxiliary electrode, a thermistor for temperature measurements and two multipurpose platinum macroelectrodes were designed and fabricated. A method for the pre-conditioning of the electrode system was developed and its success shown by electrochemical analysis and time-of-flight secondary ion mass spectrometry. After immobilizing lactate oxidase and glucose oxidase on the working electrode arrays using hydrogel, a micro flow-injection biosensor was constructed by inserting the chip-electrode into a custom made micro flow-through cell. The possibilities of online multi-analyte detection and extension of the biosensors linear range by diffusion-limiting membranes were explored. Ultrafiltration as a recently developed sampling technique and the storage of analyte in fused silica tubing has been used in combination with the micro-analysis system to create a miniaturized continuos online analysis system. After assessing the interferences when doing electrochemical measurements in human blood as sample matrix, an anti-fouling membrane was electropolymerized on the working electrode arrays. As an example for measurement of real samples, the continuous monitoring of lactate in rat interstitial fluid collected in fused silica tubing by ultrafiltration is shown. For comparison, the same experiment was run in parallel with a commercial thick film electrode system. This work shows that the techniques developed to produce and modify thin-film electrode systems with microelectrode characteristics allow the mass-production of biosensors for special applications.