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Erlangung Der Doktorwürde INAUGURAL - DISSERTATION ZUR ERLANGUNG DER DOKTORWÜRDE DER NATURWISSENSCHAFTLICH – MATHEMATISCHEN GESAMTFAKULTÄT DER RUPRECHT - KARLS - UNIVERSITÄT HEIDELBERG vorgelegt von Dipl.-Chem. Sebastian Weber aus Düsseldorf Tag der mündlichen Prüfung: 25.07.2018 Manufacturing of Gold Nanoelectrode- Ensembles for Intracellular Recording on Living Cells Referees: Prof. Dr. Joachim P. Spatz Prof. Dr. Rainer Dahint Institut für Physikalische Chemie Universität Heidelberg Institut für Physikalische Chemie Max-Planck-Institut für medizinische Universität Heidelberg Forschung, Heidelberg Meinen Eltern & Marion Abstract The investigation of electric phenomena occurring in biological cells is the subject of electrophysiological research. The discovery of ionic currents as the origin of membrane resting- and action-potentials led to a comprehensive understanding of various essential biological processes, e.g. trans-membrane transport, signal transduction in the nervous system and muscle contraction. Throughout the 20th century numerous experimental methods for observation of these phenomena have been developed and continuously improved. Precise measurements of intracellular potentials using current- and voltage-clamp based methods have become standard laboratory practice. Despite their huge success, these methods suffer from their invasive nature and inherent workload. Therefore, new methods have been sought, leading to the development of flat microelectrodes, allowing long-term stable electrical measurements with live cells and tissue samples. Arrays of flat electrodes have enabled multi-site and multi-cell measurements, but with the drawback of poor signal amplitude and signal-to-noise ratio. The continuous improvement of nanofabrication methods has enabled the fabrication of vertical nanowires. Such structures have been intensively studied in the past two decades, aiming at the design novel platforms with highly improved electrical properties for intracellular measurements. In this work, fabrication methods for gold nanoelectrode-ensembles are studied in detail. Each step of the manufacturing process for the ensembles is reviewed in detail, resulting in more efficient manufacturing of electrodes with variable diameter and length as well as significantly improving the quality of the obtained samples. The manufactured structures were tested with electrochemical impedance spectroscopy and cyclic voltammetry to evaluate their performance for intracellular recording in in-vitro experiments with live cells. VII Zusammenfassung Die Untersuchung elektrischer Phänomene in Zusammenhang mit biologischen Zellen ist Gegenstand der Elektrophysiologie. Die Entdeckung von Ionenströmen als Ursprung von Ruhe- und Aktionspotentialen ebnete den Weg für ein umfassendes Verständnis verschiedener elementarer biologischer Prozesse wie z.B. dem Transmembrantransport, der Singnalleitung in Nervenzellen und der Muskelkontraktion. Im Laufe des 20. Jahrhunderts wurden zahlreiche experimentelle Methoden zur Aufklärung dieser Prozesse entwickelt und kontinuierlich verbessert. Die präzise Messung intrazellulärer Potentiale mit Voltage- und Current-Clamp-basierten Messmethoden hat sich als gängige Laborpraxis etabliert. Trotz ihres hohen Erfolgs besitzt diese Methode jedoch einige immanente Nachteile. Sie erfordert einen sehr hohen Arbeitsaufwand und ist durch ihre invasive Natur begrenzt in der zeitlichen Ausdehnung der Messungen. Als Alternative wurde die Messung elektrischer Signale von Zellen und Gewebeproben mit flachen Mikroelektroden entwickelt. In Arrays angeordnete Mikroelektroden erlauben langzeitstabile Messungen mit hoher zeitlicher und räumlicher Auflösung, allerdings mit dem Nachteil deutlich geringerer Signalamplituden und eines erhöhten Signal-Rausch-Verhältnisses. Die kontinuierliche Verbesserung von Methoden zur Herstellung von Nanostrukturen ermöglichte die Produktion von vertikalen, freistehenden Nanodrähten. Derartig strukturierte Oberflächen kommen aufgrund ihrer deutlich verbesserten elektrischen Eigenschaften und der Möglichkeit zur Herstellung eines intrazellulären elektrischen Kontakts als Alternative zu den bisher verwendeten flachen Mikroelektroden-Arrays in Betracht. In dieser Arbeit werden Herstellungsmethoden für Nanoelektroden-Ensembles aus Gold im Detail untersucht. Alle erforderlichen Prozessschritte wurden einer eingehenden Untersuchung unterzogen, wodurch eine höhere Effizienz bei er Herstellung von Nanoelektroden mit variablem Durchmesser und Höhe bei deutlich gesteigerter Qualität. Diese Elektroden wurden in verschiedenen auf Ihre Eignung für die Messung von Spannungen und Strömen von lebenden Zellen untersucht. IX CONTENT ABSTRACT...................................................................................................................................... VII ZUSAMMENFASSUNG ......................................................................................................................IX 1 INTRODUCTION ........................................................................................................................ 1 1.1 SCOPE OF THE PROJECT ................................................................................................................. 1 1.2 BRIEF HISTORY OF ELECTROPHYSIOLOGY ............................................................................................ 4 1.3 FLAT MICROELECTRODES AND 3D-NANOSTRUCTURES FOR ELECTROPHYSIOLOGICAL RESEARCH ................... 6 1.4 LATEST DEVELOPMENTS IN (CMOS-BASED) NEAS ............................................................................. 9 1.5 BIOELECTRICITY AND BIOSENSING .................................................................................................. 13 2 THEORY ................................................................................................................................... 16 2.1 MEMBRANE POTENTIALS ............................................................................................................. 16 2.1.1 The Cellular Membrane ................................................................................................. 16 2.1.2 The Membrane Resting Potential.................................................................................. 18 2.1.3 Action Potentials ........................................................................................................... 22 2.1.4 Measurement of Membrane Potentials ........................................................................ 23 2.1.5 Intracellular Access of Nanoelectrodes ......................................................................... 25 2.2 DEPOSITION OF METALLIC THIN FILMS ........................................................................................... 28 2.2.1 Evaporation Techniques ................................................................................................ 28 2.2.2 Sputter deposition ......................................................................................................... 29 2.3 CYCLIC VOLTAMMETRY................................................................................................................ 30 2.3.1 Voltammetry Basics ...................................................................................................... 30 2.3.2 Diffusion Aspects ........................................................................................................... 32 2.4 ELECTROCHEMICAL IMPEDANCE SPECTROSCOPY ............................................................................... 35 3 MATERIALS AND METHODS .................................................................................................... 42 3.1 MANUFACTURING OF GOLD NANOELECTRODE ENSEMBLES ................................................................ 42 3.1.1 Conventional Approach for NEE manufacturing ........................................................... 43 3.1.2 Scaled-up process for NEE manufacturing .................................................................... 49 3.1.3 Manufacturing of Ag/AgCl reference electrodes .......................................................... 52 3.1.4 Assembly of experimental chambers ............................................................................ 52 3.2 ELECTROCHEMICAL ANALYSIS OF NANOELECTRODE SURFACES ............................................................. 54 XI 3.2.1 Electrochemical Impedance Measurements ................................................................. 54 3.2.2 Cyclic Voltammetry ....................................................................................................... 54 3.3 VOLTAGE AND CURRENT MEASUREMENTS ....................................................................................... 55 3.3.1 Measurement Program Layout ..................................................................................... 55 3.3.2 Device Configuration .................................................................................................... 56 3.3.3 Voltage Measurement Configuration ........................................................................... 56 3.3.4 Measurement Speed ..................................................................................................... 57 3.4 CELL CULTURE ........................................................................................................................... 59 3.4.1 Passaging of Cells ......................................................................................................... 59 3.4.2 Freezing of Cells
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