COMMUNICATION © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com (1 of 6) 1605744 Lactate Detection in Tumor Cell Cultures Using Organic Transistor Circuits Marcel Braendlein, Anna-Maria Pappa, Marc Ferro, Alexia Lopresti, Claire Acquaviva, Emilie Mamessier, George G. Malliaras, and Róisín M. Owens* M. Braendlein, A.-M. Pappa, M. Ferro, Prof. G. G. Malliaras, Prof. R. M. Owens Department of Bioelectronics Ecole Nationale Supérieure des Mines CMP-EMSE, MOC Gardanne 13541, France E-mail: owens@emse.fr A. Lopresti, Dr. C. Acquaviva, Dr. E. Mamessier INSERM U1068 Institut Paoli-Calmettes CRCM, CNRS Aix Marseille Université Marseille 13009, France DOI: 10.1002/adma.201605744 However, some key issues still impede their practical imple- mentation in a clinical setting. These issues include signal drift due to environmental changes (e.g., electrolyte evaporation, temperature changes, instability of transducer), as well as signal misinterpretation due to interference (e.g., charged species or oxidizable compounds in complex media). [13] Sensor circuits represent an elegant alternative solution, departing from a single sensor and focusing on a more complete system that can be readily intercepted with simple acquisition tools, as demon- strated by Svensson et al. [14] Recently, the organic electrochemical transistor (OECT) has drawn considerable attention as a sensing element. [15–17] In a three-terminal configuration, the active material, being com- prised of an organic semiconductor, can be electrochemically doped or dedoped through an ionic current from the electro- lyte into the polymer, thereby changing its conductivity. [18] The possibility for low voltage gating provides devices sen- sitive to biological signals that may consist of minute ionic currents. [19] OECTs have proven to outperform state-of-the- art devices such as electrodes, [20] and have been used in a wide variety of biological applications, including metabolite sensing. [21–23] Bearing in mind the complex issues related to sensitive and specific detection of metabolites of interest in pathologies such as cancer, in this article, we present an in vitro electronic plat- form for sensitive and accurate metabolite sensing in highly interfering samples, such as cell culture media. In particular, we developed a reference-based sensor circuit, by integrating two differently functionalized OECTs, comprised of the well- known organic p-type semiconductor poly(3,4-ethylenedioxythi- ophene):poly(styrene sulfonate) (PEDOT:PSS), [24] into a Wheat- stone bridge layout. The planar all-PEDOT:PSS configuration of the channel and the gate (Figure 1a) facilitates the device bio- functionalization [23] and also allows for future integration with microfluidics. For the device fabrication, a new lithographic approach based on a fluorinated photoresist, that allows for direct patterning of spun-cast PEDOT:PSS, was employed in this work (Figure S1, Supporting Information). Starting from a homogeneously coated PEDOT:PSS film and ablatively pat- terning the active areas, [25,26] a greater device homogeneity can be achieved (Figure 1b and Figure S2c, Supporting Informa- tion), contrary to the conventional Parylene-C peel-off tech- nique. [27] According to the output and transfer characteristics of the OECTs (Figure S2a,b, Supporting Information), the max- imum transconductance [28] g m = ΔI D /ΔV GS of 6.4 mS is obtained at V GS = 200 mV, which coincides with the sensor’s working potential, to ensure maximum sensitivity. By adding a drain load resistor in series with the OECT, a floating voltage point Rapid and early diagnosis of disease is known to be a significant factor in treatment and improved prognosis, notably in cancer. From the first commercialized device based on the “enzyme electrode,” introduced by Clark and Lyons, able to measure accurately glucose concentrations in whole blood samples, [1,2] to research prototypes of miniaturized epidermal sensor chips able to measure real-time multiple analytes, [3] biosensors have evolved significantly and become invaluable tools for diag- nosis of many pathologies from infections to heart disease. Remarkably, little of the progress in the field of biosensing has translated to improved diagnosis of cancer. [4] Use of biosensors in diagnostic applications requires iden- tification of a biomarker (to confer specificity) while the sen- sitivity is mostly related to the intimate coupling of a reaction involving the biomarker with a transducer. In cancer diag- nostics, clinicians are highly dependent on the identification of biomarkers that will reliably predict occurrence and recur- rence of cancerous cell populations, however such reliable bio- markers are few and far between, perhaps explaining the dearth of cancer biosensing devices. [5,6] One marked feature of cancer however, is the increased glycolytic activity associated with highly proliferative aggressive cell growth. [7] In recent years, increased metabolic activity has been suggested as a biomarker for cancer. This idea is not new, having been introduced over 60 years ago by Warburg, who predicted enhanced uptake and usage of glucose and thus production of lactate. [8] Lactate has proven to be a prognostic indicator of the degree of malignancy in primary tumors as well as of the probability of metastasis. [9] Electrical, label-free biosensing of metabolites such as glucose and lactate is known to be advantageous with regards to speed and sensitivity, and indeed the integration of biosensors with microelectronic devices has brought about multiplexed capabili- ties as well as enabling miniaturization and automation. [10–12] Adv. Mater. 2017, 29, 1605744 www.advancedsciencenews.com www.advmat.de