TY - JOUR A1 - Goßmann, Matthias A1 - Frotscher, Ralf A1 - Linder, Peter A1 - Bayer, Robin A1 - Epple, U. A1 - Staat, Manfred A1 - Temiz Artmann, Aysegül A1 - Artmann, Gerhard T1 - Mechano-pharmacological characterization of cardiomyocytes derived from human induced pluripotent stem cells JF - Cellular physiology and biochemistry N2 - Background/Aims: Common systems for the quantification of cellular contraction rely on animal-based models, complex experimental setups or indirect approaches. The herein presented CellDrum technology for testing mechanical tension of cellular monolayers and thin tissue constructs has the potential to scale-up mechanical testing towards medium-throughput analyses. Using hiPS-Cardiac Myocytes (hiPS-CMs) it represents a new perspective of drug testing and brings us closer to personalized drug medication. Methods: In the present study, monolayers of self-beating hiPS-CMs were grown on ultra-thin circular silicone membranes and deflect under the weight of the culture medium. Rhythmic contractions of the hiPS-CMs induced variations of the membrane deflection. The recorded contraction-relaxation-cycles were analyzed with respect to their amplitudes, durations, time integrals and frequencies. Besides unstimulated force and tensile stress, we investigated the effects of agonists and antagonists acting on Ca²⁺ channels (S-Bay K8644/verapamil) and Na⁺ channels (veratridine/lidocaine). Results: The measured data and simulations for pharmacologically unstimulated contraction resembled findings in native human heart tissue, while the pharmacological dose-response curves were highly accurate and consistent with reference data. Conclusion: We conclude that the combination of the CellDrum with hiPS-CMs offers a fast, facile and precise system for pharmacological, toxicological studies and offers new preclinical basic research potential. KW - Inotropic compounds KW - Pharmacology KW - Ion channels KW - CellDrum KW - Heart tissue culture KW - Induced pluripotent stem cells KW - Cardiac myocytes Y1 - 2016 U6 - http://dx.doi.org/10.1159/000443124 SN - 1421-9778 (Online) SN - 1015-8987 (Print) VL - 38 IS - 3 SP - 1182 EP - 1198 PB - Karger CY - Basel ER - TY - CHAP A1 - Suryoputri, Nathania A1 - Ghaderi, Aydin A1 - Linder, Peter A1 - Kotliar, Konstantin A1 - Göttler, Jens A1 - Sorg, Christian A1 - Grimmer, Timo ED - Erni, Daniel ED - Fischerauer, Alice ED - Himmel, Jörg ED - Seeger, Thomas ED - Thelen, Klaus T1 - Does hemodynamic response function change in Alzheimer disease? T2 - 2nd YRA MedTech Symposium 2017 : June 8th - 9th / 2017 / Hochschule Ruhr-West Y1 - 2017 SN - 978-3-9814801-9-1 U6 - http://dx.doi.org/10.17185/duepublico/43984 N1 - A young researchers track of the 7th IEEE Workshop & SENSORICA 2017 SP - 92 PB - Universität Duisburg-Essen CY - Duisburg ER - TY - PAT A1 - Artmann, Gerhard A1 - Linder, Peter A1 - Bayer, Robin A1 - Gossmann, Matthias T1 - Celldrum electrode arrangement for measuring mechanical stress [Patent of invention] N2 - The invention pertains to a CellDrum electrode arrangement for measuring mechanical stress, comprising a mechanical holder (1 ) and a non-conductive membrane (4), whereby the membrane (4) is at least partially fixed at its circumference to the mechanical holder (1), keeping it in place when the membrane (4) may bend due to forces acting on the membrane (4), the mechanical holder (1) and the membrane (4) forming a container, whereby the membrane (1) within the container comprises an cell- membrane compound layer or biological material (3) adhered to the deformable membrane 4 which in response to stimulation by an agent may exert mechanical stress to the membrane (4) such that the membrane bending stage changes whereby the container may be filled with an electrolyte, whereby an electric contact (2) is arranged allowing to contact said electrolyte when filled into to the container, whereby within a predefined geometry to the fixing of the membrane (4) an electrode (7) is arranged, whereby the electrode (7) is electrically insulated with respect to the electric contact (2) as well as said electrolyte, whereby mechanical stress due to an agent may be measured as a change in capacitance. Y1 - 2017 N1 - Patent auch unter EP3403090, CN109477828, US2019033245 und LU92948 veröffentlicht. PB - WIPO CY - Geneva ER - TY - CHAP A1 - Hunker, Jan A1 - Jung, Alexander A1 - Goßmann, Matthias A1 - Linder, Peter A1 - Staat, Manfred ED - Staat, Manfred ED - Erni, Daniel T1 - Development of a tool to analyze the conduction speed in microelectrode array measurements of cardiac tissue T2 - 3rd YRA MedTech Symposium 2019 : May 24 / 2019 / FH Aachen N2 - The discovery of human induced pluripotent stem cells reprogrammed from somatic cells [1] and their ability to differentiate into cardiomyocytes (hiPSC-CMs) has provided a robust platform for drug screening [2]. Drug screenings are essential in the development of new components, particularly for evaluating the potential of drugs to induce life-threatening pro-arrhythmias. Between 1988 and 2009, 14 drugs have been removed from the market for this reason [3]. The microelectrode array (MEA) technique is a robust tool for drug screening as it detects the field potentials (FPs) for the entire cell culture. Furthermore, the propagation of the field potential can be examined on an electrode basis. To analyze MEA measurements in detail, we have developed an open-source tool. Y1 - 2019 SN - 978-3-940402-22-6 U6 - http://dx.doi.org/10.17185/duepublico/48750 SP - 7 EP - 8 PB - Universität Duisburg-Essen CY - Duisburg ER - TY - JOUR A1 - Linder, Peter A1 - Beckler, Matthias A1 - Doerr, Leo A1 - Stoelzle-Feix, Sonja A1 - Fertig, Niels A1 - Jung, Alexander A1 - Staat, Manfred A1 - Gossmann, Matthias T1 - A new in vitro tool to investigate cardiac contractility under physiological mechanical conditions JF - Journal of Pharmacological and Toxicological Methods Y1 - 2019 U6 - http://dx.doi.org/10.1016/j.vascn.2019.05.162 SN - 1056-8719 VL - 99 IS - Article number 106595 PB - Elsevier CY - Amsterdam ER - TY - RPRT A1 - Stölzle-Feix, Sonja A1 - Thomas, Ulrich A1 - Engelstädter, Max A1 - Goßmann, Matthias A1 - Linder, Peter A1 - Staat, Manfred A1 - Raman, Aravind Hariharan A1 - Jung, Alexander A1 - Fertig, Niels T1 - Plattformtechnologie für kardiale Sicherheitspharmakologie basierend auf teilsynthetischem Herzmuskelgewebe (FLEXcyte) : gemeinsamer FuE-Abschlussbericht aller Partner des Verbundprojektes : Projektlaufzeit: 01.10.2018 bis 30.09.2020 Y1 - 2021 U6 - http://dx.doi.org/10.2314/KXP:1813208581 N1 - Förderkennzeichen BMBF 02P18K020-021 Verbundnummer 01185221 PB - Nanion Technologies GmbH CY - München ER - TY - JOUR A1 - Hunker, Jan L. A1 - Gossmann, Matthias A1 - Raman, Aravind Hariharan A1 - Linder, Peter T1 - Artificial neural networks in cardiac safety assessment: Classification of chemotherapeutic compound effects on hiPSC-derived cardiomyocyte contractility JF - Journal of Pharmacological and Toxicological Methods Y1 - 2021 U6 - http://dx.doi.org/10.1016/j.vascn.2021.107044 SN - 1056-8719 VL - 111 IS - Article number 107044 PB - Elsevier CY - New York ER - TY - JOUR A1 - Gossmann, Matthias A1 - Thomas, Ulrich A1 - Horváth, András A1 - Dragicevic, Elena A1 - Stoelzle-Feix, Sonja A1 - Jung, Alexander A1 - Raman, Aravind Hariharan A1 - Staat, Manfred A1 - Linder, Peter T1 - A higher-throughput approach to investigate cardiac contractility in vitro under physiological mechanical conditions JF - Journal of Pharmacological and Toxicological Methods Y1 - 2020 U6 - http://dx.doi.org/10.1016/j.vascn.2020.106843 VL - 105 IS - Article 106843 PB - Elsevier CY - New York, NY ER - TY - JOUR A1 - Knox, Ronald A1 - Bruggemann, Andrea A1 - Gossmann, Matthias A1 - Thomas, Ulrich A1 - Horváth, András A1 - Dragicevic, Elena A1 - Stoelzle-Feix, Sonja A1 - Fertig, Niels A1 - Jung, Alexander A1 - Raman, Aravind Hariharan A1 - Staat, Manfred A1 - Linder, Peter T1 - Combining physiological relevance and throughput for in vitro cardiac contractility measurement JF - Biophysical Journal N2 - Despite increasing acceptance of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in safety pharmacology, controversy remains about the physiological relevance of existing in vitro models for their mechanical testing. We hypothesize that existing signs of immaturity of the cell models result from an improper mechanical environment. We cultured hiPSC-CMs in a 96-well format on hyperelastic silicone membranes imitating their native mechanical environment, resulting in physiological responses to compound stimuli.We validated cell responses on the FLEXcyte 96, with a set of reference compounds covering a broad range of cellular targets, including ion channel modulators, adrenergic receptor modulators and kinase inhibitors. Acute (10 - 30 min) and chronic (up to 7 days) effects were investigated. Furthermore, the measurements were complemented with electromechanical models based on electrophysiological recordings of the used cell types.hiPSC-CMs were cultured on freely-swinging, ultra-thin and hyperelastic silicone membranes. The weight of the cell culture medium deflects the membranes downwards. Rhythmic contraction of the hiPSC-CMs resulted in dynamic deflection changes which were quantified by capacitive distance sensing. The cells were cultured for 7 days prior to compound addition. Acute measurements were conducted 10-30 minutes after compound addition in standard culture medium. For chronic treatment, compound-containing medium was replaced daily for up to 7 days. Electrophysiological properties of the employed cell types were recorded by automated patch-clamp (Patchliner) and the results were integrated into the electromechanical model of the system.Calcium channel agonist S Bay K8644 and beta-adrenergic stimulator isoproterenol induced significant positive inotropic responses without additional external stimulation. Kinase inhibitors displayed cardiotoxic effects on a functional level at low concentrations. The system-integrated analysis detected alterations in beating shape as well as frequency and arrhythmic events and we provide a quantitative measure of these. Y1 - 2020 U6 - http://dx.doi.org/10.1016/j.bpj.2019.11.3104 SN - 0006-3495 N1 - Raman, Arayind Hariharan im Artikel unter dem Namen: Raman, Alexander H. VL - 118 IS - Issue 3, Supplement 1 SP - 570a PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Kurz, R. A1 - Linder, Peter A1 - Trzewik, Jürgen A1 - Rüffer, M. A1 - Artmann, Gerhard A1 - Digel, Ilya A1 - Rothermel, A. A1 - Robitzki, A. A1 - Temiz Artmann, Aysegül T1 - Contractile tension and beating rates of self-exciting monolayers and 3D-tissue constructs of neonatal rat cardiomyocytes JF - Medical and Biological Engineering and Computing N2 - The CellDrum technology (The term 'CellDrum technology' includes a couple of slightly different technological setups for measuring lateral mechanical tension in various types of cell monolayers or 3D-tissue constructs) was designed to quantify the contraction rate and mechanical tension of self-exciting cardiac myocytes. Cells were grown either within flexible, circular collagen gels or as monolayer on top of respective 1-mum thin silicone membranes. Membrane and cells were bulged outwards by air pressure. This biaxial strain distribution is rather similar the beating, blood-filled heart. The setup allowed presetting the mechanical residual stress level externally by adjusting the centre deflection, thus, mimicking hypertension in vitro. Tension was measured as oscillating differential pressure change between chamber and environment. A 0.5-mm thick collagen-cardiac myocyte tissue construct induced after 2 days of culturing (initial cell density 2 x 10(4) cells/ml), a mechanical tension of 1.62 +/- 0.17 microN/mm(2). Mechanical load is an important growth regulator in the developing heart, and the orientation and alignment of cardiomyocytes is stress sensitive. Therefore, it was necessary to develop the CellDrum technology with its biaxial stress-strain distribution and defined mechanical boundary conditions. Cells were exposed to strain in two directions, radially and circumferentially, which is similar to biaxial loading in real heart tissues. Thus, from a biomechanical point of view, the system is preferable to previous setups based on uniaxial stretching. Y1 - 2010 U6 - http://dx.doi.org/10.1007/s11517-009-0552-y SN - 1741-0444 VL - 48 IS - 1 SP - 59 EP - 65 PB - Springer Nature CY - Cham ER -