Enhancement of Cardiac Contractility Using Gold-coated SU-8 Cantilevers and Their Application to Drug-induced Cardiac Toxicity Tests

The Analyst ◽  
2021 ◽  
Author(s):  
Jong Yun Kim ◽  
Arunkumar Shanmugasundaram ◽  
Dong-Weon Lee
Keyword(s):  
Cardiac Toxicity ◽  
Cardiac Contractility ◽  
Toxicity Tests ◽  
Drug Induced

Herein, we propose an array of gold (Au)-coated SU-8 cantilevers with microgrooves for improved maturation of cardiomyocytes and describe its applications to drug-induced cardiac toxicity tests. Firstly, we evaluated the...

scholarly journals Polymer-Based Functional Cantilevers Integrated with Interdigitated Electrode Arrays—A Novel Platform for Cardiac Sensing

Micromachines ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 450 ◽  
Author(s):  
Pooja P. Kanade ◽  
Nomin-Erdene Oyunbaatar ◽  
Dong-Weon Lee
Keyword(s):  
Cardiac Toxicity ◽  
Toxicity Tests ◽  
Dual Function ◽  
Electrode Arrays ◽  
Contraction Force ◽  
Drug Induced ◽  
Cantilever Deflection ◽  
Biomedical Device ◽  
Photosensitive Polymer ◽  
Common Causes

Heart related ailments are some of the most common causes for death in the world, and some of the causes are cardiac toxicity due to drugs. Several platforms have been developed in this regard over the years that can measure electrical or mechanical behavior of cardiomyocytes. In this study, we have demonstrated a biomedical device that can simultaneously measure electrophysiology and contraction force of cardiomyocytes. This dual-function device is composed of a photosensitive polymer-based cantilever, with a pair of metal-based interdigitated electrodes on its surface, such that the cantilever can measure the contraction force of cardiomyocytes and the electrodes can measure the impedance between cells and substrate. The cantilever is patterned with microgrooves so that the cardiomyocytes can align to the cantilever in order to make a higher cantilever deflection in response to contraction force. Preliminary experimental results have identified the potential for use in the drug-induced cardiac toxicity tests, and further optimization is desirable to extend the technique to various bio-sensor areas.

Drug-induced cardiac toxicity: emphasizing the role of electrocardiography in clinical research and drug development

2004 ◽  
Vol 37 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Ihor Gussak ◽  
Jeffrey Litwin ◽  
Robert Kleiman ◽  
Scott Grisanti ◽  
Joel Morganroth
Keyword(s):  
Drug Development ◽  
Clinical Research ◽  
Cardiac Toxicity ◽  
Drug Induced

scholarly journals Intermittent Starvation Extends the Functional Lifetime of Primary Human Hepatocyte Cultures

2020 ◽  
Vol 174 (2) ◽  
pp. 266-277
Author(s):  
Matthew D Davidson ◽  
Salman R Khetani
Keyword(s):  
Drug Exposure ◽  
Adenosine Monophosphate ◽  
Human Hepatocyte ◽  
Toxicity Tests ◽  
Drug Induced ◽  
Nonparenchymal Cells ◽  
Primary Human Hepatocyte ◽  
Serum Hormone

Abstract Primary human hepatocyte (PHH) cultures have become indispensable to mitigate the risk of adverse drug reactions in human patients. In contrast to dedifferentiating monocultures, coculture with nonparenchymal cells maintains PHH functions for 2–4 weeks. However, because the functional lifespan of PHHs in vivo is 200–400 days, it is desirable to further prolong PHH functions in vitro toward modeling chronic drug exposure and disease progression. Fasting has benefits on the longevity of organisms and the health of tissues such as the liver. We hypothesized that a culturing protocol that mimics dynamic fasting/starvation could activate starvation pathways and prolong PHH functional lifetime. To mimic starvation, serum and hormones were intermittently removed from the culture medium of micropatterned cocultures (MPCCs) containing PHHs organized onto collagen domains and surrounded by 3T3-J2 murine fibroblasts. A weekly 2-day starvation optimally prolonged PHH functional lifetime for 6+ weeks in MPCCs versus a decline after 3 weeks in nonstarved controls. The 2-day starvation also enhanced the functions of PHH monocultures for 2 weeks, suggesting direct effects on PHHs. In MPCCs, starvation activated 5' adenosine monophosphate-activated protein kinase (AMPK) and restricted fibroblast overgrowth onto PHH islands, thereby maintaining hepatic polarity. The effects of starvation on MPCCs were partially recapitulated by activating AMPK using metformin or growth arresting fibroblasts via mitomycin-C. Lastly, starved MPCCs demonstrated lower false positives for drug toxicity tests and higher drug-induced cytochrome-P450 activities versus nonstarved controls even after 5 weeks. In conclusion, intermittent serum/hormone starvation extends PHH functional lifetime toward enabling clinically relevant drug screening.

An in vitro platform using the human and rat primary cardiomyocyte work loop assay to screen for drug-induced effects on cardiac contractility

2020 ◽  
Vol 105 ◽  
pp. 106759
Author(s):  
Mayel Gharanei ◽  
Jeremy Billson ◽  
Oana Blair ◽  
Josh Hurst ◽  
Adam Linekar ◽  
...  
Keyword(s):  
Cardiac Contractility ◽  
Drug Induced ◽  
Work Loop

scholarly journals Computational investigation of drug-induced effects on human cardiac electro-mechanics

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
E Passini ◽  
F Margara ◽  
B Rodriguez
Keyword(s):  
Experimental Data ◽  
Action Potential ◽  
Cardiac Contractility ◽  
Calcium Transient ◽  
Inotropic Effect ◽  
Active Force ◽  
Computational Investigation ◽  
Drug Induced ◽  
Virtual Population ◽  
Simulation Results

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NC3Rs Infrastructure for Impart Award (NC/P001076/1) Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences (214290/Z/18/Z) Background Human-based computer modelling and simulations have been widely used in cardiac electrophysiology, to provide a better understanding of the ionic mechanisms underlying risk of arrhythmias, and their modulation by drugs and diseased conditions. More recently, multiscale computer models of human cardiac electro-mechanics have been developed. These models provide the means for a comprehensive investigation of action potential, calcium transient, active force, and their variability in the population, and can predict drug-induced contractility changes in humans. Purpose This study aims to perform a computational investigation of variability in human cardiac contractility biomarkers and their modulation by well-known drugs. Methods We considered the most recent model of human ventricular electro-mechanics (Margara et al. 2020). We constructed a population of 300 cells by randomly varying the main ionic currents in the model, to represent the biological variability observed in human experimental data. We then simulated the effect of 10 reference compounds, 6 of which with known pro-arrhythmic risk. Simulations were performed at 1 Hz for multiple drug concentrations, using the Virtual Assay software. A set of action potential, calcium transient and active force biomarkers were computed, as well as the electro-mechanical window, and the occurrence of early after-depolarisations and after-contractions in the virtual population. Simulation results were compared against clinical risk of drug-induced arrhythmias and experimental recording from human ventricular myocytes from literature. Results Overall, biomarker variability in the virtual population increased following drug application compared to control conditions. All compounds had a negative inotropic effect in simulation, with a marked decrease of the active tension peak, e.g. -80% for nifedipine 8 nM. This is in agreement with human experimental data for all compounds except Dofetilide, for which no inotropic effect was observed in vitro. Compounds with known risk of arrhythmias provoked early after-depolarisations, which in turn caused after-contractions. Their occurrence in the population increased together with the drug concentration, e.g. 3.6% at 0.16 µM and 48% at 0.48 µM for droperidol. In addition, these compounds also displayed prolonged action potential and calcium transient, and a shortening of the electro-mechanical window, all known biomarkers of pro-arrhythmia. Conclusions We evaluated the effect and the cardiac safety of 10 reference compounds in a population of 300 human ventricular electro-mechanical models. Simulation results were in good agreement with experimental data in human ventricular cardiomyocytes, and they allowed to identify the compounds with a known pro-arrhythmic risk based on drug-induced early after-depolarisations and after-contractions. This methodology provides new insights into variability in human cardiac contractility and its modulation by drugs.

Serum Troponins as Biomarkers of Drug-Induced Cardiac Toxicity

2004 ◽  
Vol 32 (1) ◽  
pp. 106-121 ◽  
Author(s):  
Kendall B. Wallace ◽  
Elizabeth Hausner ◽  
Eugene Herman ◽  
Gordon D. Holt ◽  
James T. Macgregor ◽  
...  
Keyword(s):  
Cardiac Toxicity ◽  
Drug Induced
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