Ultrathin and Flexible Bioelectronic Arrays for Functional Measurement of iPSC-Cardiomyocytes under Cardiotropic Drug Administration and Controlled Microenvironments

Abstract

Emerging heart-on-a-chip technology is a promising tool to establish in vitro cardiac models for therapeutic testing and disease modeling. However, due to the technical complexity of integrating cell culture chambers, biosensors, and bioreactors into a single entity, a microphysiological system capable of reproducing controlled microenvironmental cues to regulate cell phenotypes, promote iPS-cardiomyocyte maturity, and simultaneously measure the dynamic changes of cardiomyocyte function in situ is not available. This paper reports an ultrathin and flexible bioelectronic array platform in 24-well format for higher-throughput contractility measurement under candidate drug administration or defined microenvironmental conditions. In the array, carbon black (CB)-PDMS flexible strain sensors were embedded for detecting iPSC-CM contractility signals. Carbon fiber electrodes and pneumatic air channels were integrated to provide electrical and mechanical stimulation to improve iPSC-CM maturation. Performed experiments validate that the bioelectronic array accurately reveals the effects of cardiotropic drugs and identifies mechanical/electrical stimulation strategies for promoting iPSC-CM maturation.

iPSC-cardiomyocytes in the preclinical prediction of candidate pharmaceutical toxicity

“…Adrenergic signaling in iPSC-CM is similar to adult human CMs. Isoproterenol, a canonical β-adrenergic agonist, induces a predictable positive chronotropic (two-fold increase in beating rate at 1 μM drug concentration) and inotropic (contractility) response ( Zhang et al, 2009 ; Wang et al, 2018 ; Dou et al, 2023 ). However, a major difference between iPSC-CMs and in vivo CM response is that the positive chronotropic and inotropic effect of isoproterenol is primarily modulated through β2 adrenergic receptors in unmatured iPSC-CMs ( Wu et al, 2015 ), compared to β1 receptors in the human heart ( Bristow et al, 1986 ; Myagmar et al, 2017 ).…”

Heart-on-a-chip systems: disease modeling and drug screening applications

“…To reduce time-to-market and improve success rate, HoC systems could provide a valuable link between pre-clinical animal studies and clinical trials or even serve as a standalone replacement to animal studies all together. One of the most popular drugs tested with HoC systems is the non-selective β-adrenergic receptor agonist isoproterenol, [143][144][145]155,160,168,172,181,224,225,[357][358][359][360][361][362][363][364][365][366][367][368] which can help treat bradycardia. Isoproterenol is similar in structure and function to epinephrine, which has also been evaluated using HoC systems.…”

“…Many of the proarrhythmic drugs block one or more of the ion channels found in the heart (K + , Na + , Ca 2+ ), making HoC systems well-suited to study their effects. Examples include verapamil (a Ca 2+ channel blocker), 168,180,182,183,360,365,366,369,[391][392][393][394] quinidine (Na + -channel blocker), 182,359,392,395 E-4031 (hERG K + -channel blocker), 180,359,360,363,[396][397][398] sotalol (K + -channel blocker), 391 nifedipine (a Ca 2+ -channel blocker), 305,361,396,397 ranolazine (Na +channel blocker), 396 flecainide (Na + -channel blocker), 362,397,398 tetrodotoxin (Na + -channel blocker), 398 ouabain (Na + /K + -ATPase blocker), 359 ATX-II (Na + -channel blocker), 359 and dofetilide (K +channel blocker). 359,395 The Lee group has developed various iterations of cantilever-based sensors to monitor real-time changes in contractile function after exposing cardiac tissue to different concentrations of drugs known to be cardiotoxic, including quinidine, E-4031, and verapamil.…”

“…acetaminophen 166,412 and diclofenac 412 ), myosin modulators ( e.g. blebbistatin 363,364 and omecamtiv mecarbil 364 ), anti-fibrotics 286 ) beta blockers, 181,362 prokinetics, 398 phosphodiesterase inhibitors, 421 hormones, 144 and nanomaterials. 379,422 Although this is a small sampling of the many therapeutics in pre-clinical studies, clinical trials, and on the market, it highlights the broad range of drug types that could potentially be studied using HoC systems.…”

Outstanding Synergy of Sensitivity and Linear Range Enabled by Multigradient Architectures

“…Flexible pressure sensors that transduce the external forces into electrical signals endow intelligent robotics, artificial prosthetics, wearable electronics, and human-machine interfaces with mechanosensory functions. − Mechanical inputs from the environment are converted to real-time electrical signals by distinct types of pressure sensors, including capacitive, − piezoelectric, − triboelectric, − and piezoresistive sensors. − A piezoresistive sensor that transduces pressure stimuli to resistance/current signals presents the advantages of simple structures and manufacturing processes, easy signal collection and readout mechanisms, and cost-effectiveness in fabrication. To meet the application requirements in complex scenarios, the pressure sensor often requires high sensitivity, excellent linearity over a broad pressure range, and high pressure resolution. ,,− Much effort has been devoted to engineering the active materials with surface micro/nanostructures, such as dome/pyramid/cone/pillar arrays, for improving the sensitivity and simultaneously broadening the pressure range. − Although encouraging progress has been made, the pressure sensors often possess varying sensitivity values within different pressure ranges due to the structural stiffening of such microstructures and corresponding signal attenuation with increasing pressure.…”