These cellular responses and the accompanying changes of physicochemical parameters are what is to be detected and transferred into a measurable electrical signal by the transducer units of the label-free biosensor devices (Fig. 1-1). There are various types of transducers, distinguishable by the underlying physicochemical phenomenon: electrochemical (including potentiometric, amperometric, and impedimetric), optical, thermometric, piezoelectric, and magnetic transduction. [8] Tab. 1-1 gives an
LAPSLight-addressable potentiometric sensors (LAPSs) are multilayer field-effect devices similar to ISFETs [66] . A LAPS consists of a doped semiconductor covered with an insulator layer and a chemosensitive layer. The device is immersed in an electrolyte solution. The semiconductor is connected with a reference electrode in contact with the electrolyte (Fig. 1-2 B; reviewed in [10,17,[67][68][69][70] with respect to biological and cell-based applications). The insulator material of LAPSs is typically made up either of a single SiO 2 layer 1.1 Label-free Biosensors for Cell-based Assays 7 chip-based systems for the label-free and continuous monitoring of DO in cell-based assays, i.e. the oxygen consumption rate (OCR) of cells. [47,48,50,53,54,57,[60][61][62] The sensor chips with integrated amperometric oxygen sensors are typically build up as multi-parametric sensors and contain further physicochemical transducer structures like e.g. for cell morphology testing and ECAR monitoring. Besides the direct measurement of DO, the amperometric sensors are also capable of sensing indirectly any species that is consumed or produced in an oxidase-based enzymatic reaction (amperometric enzyme sensor) via the oxygen or hydrogen peroxide concentration. For this purpose, the amperometric pO 2 sensor is coated with a layer in which the respective enzyme is immobilized and which enables free diffusion of all reactants between the bulk solution and the sensor surface. This approach was first presented by Clark and Lyons as an amperometric sensor for glucose [85] and has also been applied as transduction method in cell-based assays for the label-free determination and monitoring of glucose and lactose [78,79] . A list of physiologically relevant analytes that have been successfully monitored by amperometric enzyme sensors is given in [86] .
ECISElectrical impedance-based sensing of adherent cells, also termed as electric cell-substrate impedance sensing (ECIS), utilizes the property of cells to impede AC current flow when they are in close contact to the substrate, i.e. a small gold-film working electrode (Fig. 1-2 D). This technique was presented first by Giaever and Keese in 1984 [87] as "morphological biosensor for mammalian cells" [88] . The principle of ECIS, the method of impedance spectroscopy, and the analysis, physiological meaning, and modeling of impedance data are extensively addressed in the methods section 3.4 Electric Cell-Substrate Impedance Sensing (ECIS). Briefly summarized, ECIS enables the time-resolved, label-free, and ...