A Bioprinted Heart-on-a-Chip with Human Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Evaluation

Abstract

In this work, we show that valve-based bioprinting induces no measurable detrimental effects on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The aim of the current study was three-fold: first, to assess the response of hiPSC-CMs to several hydrogel formulations by measuring electrophysiological function; second, to customise a new microvalve-based cell printing mechanism in order to deliver hiPSC-CMs suspensions, and third, to compare the traditional manual pipetting cell-culture method and cardiomyocytes dispensed with the bioprinter. To achieve the first and third objectives, iCell2 (Cellular Dynamics International) hiPSC-CMs were used. The effects of well-known drugs were tested on iCell2 cultured by manual pipetting and bioprinting. Despite the results showing that hydrogels and their cross-linkers significantly reduced the electrophysiological performance of the cells compared with those cultured on fibronectin, the bio-ink droplets containing a liquid suspension of live cardiomyocytes proved to be an alternative to standard manual handling and could reduce the number of cells required for drug testing, with no significant differences in drug-sensitivity between both approaches. These results provide a basis for the development of a novel bioprinter with nanolitre resolution to decrease the required number of cells and to automate the cell plating process.

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

“…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.…”

“…5c). Using this technology, the group measured various forms of arrhythmia, including prolonged beating duration caused by E-4031, 180,359,360,363,[396][397][398] decreased contraction force and bradycardia after verapamil and lidocaine exposure, 180,182,183,391,392 early after depolarization (EAD) and TdP at high quinidine levels. 182,392 Given that arrhythmia is typically detected using electrocardiogram (ECG) and arises due to a dysfunctional conduction system, electrical measurements are well-suited to record drug-induced changes in field potential duration (FPD), which is analogous to the QT interval used in the clinic.…”

“…The cardiotoxicity of various other classes of drugs and nanomaterials has been studied using HoC systems, including antihistamines (e.g. terfenidine, 172,378 astemizole, 393 and fexodenadine 172 ), anesthetics 361,371,393,397 ) steroids (e.g. dexamethasone 144 and hydrocortisone 412 ), anti-depressants 420 ) pain relievers (e.g.…”

Microfluidic Organ-on-a-Chip System for Disease Modeling and Drug Development

“…This can be used for drug screening when it is cultured in a microfluidic perfusion bioreactor. Alan et al have recently shown that alginate and cross-linking agent precursor solutions have deleterious effects on cardiomyocytes [ 45 ]. The bioink for bioprinting contains alginate, which has been gelated, but it remains to be seen whether it will affect cardiomyocytes when tested in microfluidic bioreactors.…”

Application of hiPSC as a Drug Tester Via Mimicking a Personalized Mini Heart

“…The interest in reprogramming cell fate has led to a revolutionary change in regenerative medicine, which achieves a “copy-paste” of patient-specific genotype cells from the bench to the bedside ( Carvajal-Vergara et al, 2010 ; Itzhaki et al, 2011 ; Yazawa et al, 2011 ; Kim et al, 2013 ). In the past decade, researchers in the field of hIPSC have attempted to solve a series of fundamental issues, including whether hIPSC have the ability to differentiate into different types of functional cells ( Ramalho-Santos, 2009 ; Maher, 2013 ; Zhao et al, 2019 ; Cowan et al, 2020 ; Lee et al, 2022 ); whether hIPSC-derived cells could mimic pathophysiological processes; and whether this completely “ in vitro ” model could help researchers unravel underlying pathogenetic mechanisms and provide clues on diagnostic and therapeutic choices ( Pavez-Giani and Cyganek, 2021 ; Faulkner-Jones et al, 2022 ; Yang et al, 2022 ). Along with their performance in several functional tests, hIPSC-derived cells show unique advantages, although even fully mature tissue characteristics still cannot be achieved today.…”