Tissue engineering the cardiac microenvironment: Multicellular microphysiological systems for drug screening

Abstract

The ability to accurately detect cardiotoxicity has become increasingly important in the development of new drugs. Since the advent of human pluripotent stem cell-derived cardiomyocytes, researchers have explored their use in creating an in vitro drug screening platform. Recently, there has been increasing interest in creating 3D microphysiological models of the heart as a tool to detect cardiotoxic compounds. By recapitulating the complex microenvironment that exists in the native heart, cardiac microphysiological systems have the potential to provide a more accurate pharmacological response compared to current standards in preclinical drug screening. This review aims to provide an overview on the progress made in creating advanced models of the human heart, including the significance and contributions of the various cellular and extracellular components to cardiac function.

3D bioprinting for cardiovascular regeneration and pharmacology

“…The heart wall contains three layers: (i) the inner endocardium, which is primarily composed of endothelial cells (ECs) and acts as a blood–heart barrier; (ii) the middle myocardium, which contains 2–4 billion CMs associating with ECs and is the thick muscular layer responsible for contraction and relaxation of the heart; and (iii) the outer epicardium/pericardium, which is a double-walled fibroserous sac that serves to protect the heart tissue [42,49]. In the myocardium, there is a high-density capillary network (3000/mm 2 ) which exists to ensure the metabolic activity of myocardium contraction, and the distance between CMs and ECs is no >2–3μm [12]. Adjacent CMs form intercalated disks, whereby intercellular junctions promote synchronous contractions via electrical coupling [12].…”

“…In the myocardium, there is a high-density capillary network (3000/mm 2 ) which exists to ensure the metabolic activity of myocardium contraction, and the distance between CMs and ECs is no >2–3μm [12]. Adjacent CMs form intercalated disks, whereby intercellular junctions promote synchronous contractions via electrical coupling [12]. Further, the spiral arrangement of ventricular myocardial fibers allows coordinated force generation adequate to pump blood to the rest of the body.…”

“…Alternatively, micro-physiological models of the heart have targeted the myocardium, the source of electrical propagation and force generation in the ventricles, as the minimal functional unit that could successfully model drug responses, disease states, and potential disease treatments [12]. 3D bioprinting offers a unique approach for generating this minimal cardiovascular functional unit, which can recapitulate the complex structure and functions of in vivo cardiac tissues with considerable fidelity.…”

“…The current approach for preclinical drug screening is through the utilization of animal models (primarily murine). However, it is these significant anatomical and physiological differences between the murine and human cardiovascular systems, such as in tissue structure, heart beating rate, and electrophysiological properties, which often leads to inaccurate predictions of the human cardiac tissue's response to various drug formulations [2,12]. Additionally, increasing ethical concerns for animal usage in cardiovascular therapeutics research should be considered as well [12].…”

“…As a promising alternative, cardiovascular tissue engineering is being explored to restore cardiac functionality, and replace abnormal or necrotic cardiovascular tissues [4,9]. Based on an understanding of the pathogeneses of various CVDs, engineered cardiac tissue constructs can also serve as in vitro micro-physiological models for drug screening and disease detection [2,10–12]. Compared to the inconsistencies of two-dimensional (2D) cell-culture and animal models, the engineering of 3D microenvironments is better suited to replicate the substantial cell-cell and cell-matrix interactions of native human tissues [13,14].…”