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Cell based AFM biosensing for screening of pulmonary drug related arrhythmic effects.

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PEŠL Martin PŘIBYL Jan KLIMOVIČ Šimon ŠČUREK Martin BECKEROVÁ Deborah BRAT Kristián SKLÁDAL Petr ROTREKL Vladimír

Rok publikování 2020
Druh Článek ve sborníku
Konference Nanocon 2020
Citace
www https://www.confer.cz/nanocon/2020
Doi http://dx.doi.org/10.37904/nanocon.2020.3745
Klíčová slova Cardiomyocyte; contraction; arrhythmia; in vitro modeling; drug adverse events; pulmonary drugs
Popis Atomic force microscopy (AFM) combined with stem cell derived human cardiomyocytes (CM) enables dynamic follow-up of cardiac contractions (e.g. beating rate, contraction and relaxation times), simultaneously with other CM biomechanical properties. Today, majority of drugs entering clinical usage needs to be tested for adverse arrhythmic effects; nevertheless, the effects on cardiomyocyte contraction are not routinely employed, only when related to cardiac pathologies. AFM-based biosensor allows in-vitro disease modeling, but also enables to monitor the effect of CM-contraction affecting drugs. Until today only few selected drugs modulating contractility and spontaneous pacing were described in animal models. This work for the first time demonstrates that basic biomechanical parameters, such as average value of contraction force and the beat rate, represent valuable pharmacological indicators of different phenotypic effects on cells without genetic burden. The presented method is robust and has low computational requirements, while keeping optimal spatial sensitivity (force detection limit 200 pN, corresponding to 20 nm displacement). The cardiac stimulating activities of drugs utilized in pneumology as aminophylline, ipratropium, and salbutamol were tested. Stimulating drugs, e.g. methylxanthines and caffeine, presented aberrant cardiomyocyte response, confirming arrhythmogenic potential, and force related fluctuations. Quantification of spontaneous contraction irregularities and related contractility changes allow precise scaling of potential negative effects adding new safety level to clinically relevant drug testing. AFM combined with human CMs serve as robust real-time screening platform for effects of pulmonary drugs. Here we describe changes in CM contractility, which is hard to describe by other screening methods and was never tested with described medication.
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