Electrical Stimulation of Artificial Heart Muscle: A Look Into the Electrophysiologic and Genetic Implications

Abstract

Development of tissue-engineered hearts for treatment of myocardial infarction or biological pacemakers has been hindered by the production of mostly arrhythmic or in-synergistic constructs. Electrical stimulation (ES) of these constructs has been shown to produce tissues with greater twitch force and better adrenergic response. In order to further our understanding of the mechanisms underlying the effect of ES, we fabricated a bioreactor capable of delivering continuous or intermittent waveforms of various types to multiple constructs simultaneously. In this study, we examined the effect of an intermittent biphasic square wave on our artificial heart muscle (AHM) composed of neonatal rat cardiac cells and fibrin gel. Twitch forces, spontaneous contraction rates, biopotentials, gene expression profiles, and histological observations were examined for the ES protocol over a 12 day culture period. We demonstrate improved consistency between samples for twitch force and contraction rate, and higher normalized twitch force amplitudes for electrically stimulated AHM. Improvements in electrophysiology within the AHM was noted by higher conduction velocities and lower latency in electrical response for electrically stimulated AHM. Genes expressing key electrophysiological and structural markers peaked at days 6 and 8 of culture, only a few days after the initiation of ES. These results may be used for optimization strategies to establish protocols for producing AHM capable of replacing damaged heart tissue in either a contractile or electrophysiological capacity. Optimized AHM can lead to alternative treatments to heart failure and alleviate the limited donor supply crisis.

Gate Mechanism and Parameter Analysis of Anodal-First Waveforms for Improving Selectivity of C-Fiber Nerves

“…It has been shown that this ISI needs to be less than 10 ms and greater than 6 ms to meet the safety requirements of biphasic stimulation. 47 The aim of adding ISI into the cathodal-first stimulation waveform is to reduce the threshold strength of the following anodal stimulation. 47 However, to guarantee the safety of stimulation, the interval between cathodal and anodal stimuli cannot be too large.…”

“… 47 The aim of adding ISI into the cathodal-first stimulation waveform is to reduce the threshold strength of the following anodal stimulation. 47 However, to guarantee the safety of stimulation, the interval between cathodal and anodal stimuli cannot be too large. Therefore, choosing an appropriate duration of ISI is vital to improve the effect of cathodal-first stimulation.…”

Artificial Scaffolds in Cardiac Tissue Engineering

“…In the search for natural biomaterials, researchers have investigated the individual components of the ECM as platforms. Many biomaterials for scaffold construction, such as collagen, fibrinogen, silk, alginate, and chitosan, are under investigation [ 53 , 93 , 94 , 95 , 96 ].…”

“…Even though they are not exclusive to collagen, cardiac patches have unique properties. One such feature is their potential to cultivate cells ex vivo to promote proper invasion of the patch; further, these patches can go into models and have high engraftment levels [ 93 ]. Lastly, a 3D collagen type I matrix seeded with autologous bone marrow mononuclear cells (for the regeneration of ischemic myocardium) showed increased thickness of the infarct scar with viable tissue and helped normalize cardiac wall stress in injured regions, limiting ventricular remodeling and improving diastolic function [ 103 ].…”

“…Previous work has used collagen and fibrin/fibrinogen patches to enhance cardiac cell maturation by simulating cardiac muscle development [ 93 , 94 ]. One clear advantage of these materials is their help in promoting electrical conductivity, particularly in differentiating cells and other stimulants.…”