Engineered models of the human heart: Directions and challenges

Abstract

Human heart (patho)physiology is now widely studied using human pluripotent stem cells, but the immaturity of derivative cardiomyocytes has largely limited disease modeling to conditions associated with mutations in cardiac ion channel genes. Recent advances in tissue engineering and organoids have, however, created new opportunities to study diseases beyond ''channelopathies.'' These synthetic cardiac structures allow quantitative measurement of contraction, force, and other biophysical parameters in three-dimensional configurations, in which the cardiomyocytes in addition become more mature. Multiple cardiac-relevant cell types are also often combined to form organized cardiac tissue mimetic constructs, where cell-cell, cell-extracellular matrix, and paracrine interactions can be mimicked. In this review, we provide an overview of some of the most promising technologies being implemented specifically in personalized heart-on-a-chip models and explore their applications, drawbacks, and potential for future development.

A New Versatile Platform for Assessment of Improved Cardiac Performance in Human-Engineered Heart Tissues

“…Since EHTs in MM+HS performed best, future improvements of culture medium could be made by evaluating which factors in horse serum contribute to a better performance. The design of the EHT platform enabled us to rapidly screen multiple culture medium conditions, a trait that makes it well-suited to systematically study other maturation factors, such as the effect of multicellularity in various ratios and both combinations and adaptations in energy sources as already described [13,[42][43][44], with contractile force as a major functional readout. Improvements in developing robust and mature hiPSC-EHTs will not only lead to a better understanding of the underlying mechanisms of cardiac maturation but will also serve as a platform for studying contractile function in patient-specific diseases, which, in addition to the cardiovascular field, can also be extended to the skeletal muscle field.…”

High-Resolution Imaging for the Analysis and Reconstruction of 3D Microenvironments for Regenerative Medicine: An Application-Focused Review

“…Optical microscopy methods are used to study the morphology and function of EHTs. In heart-on-a-chip (HoC) devices, an optical window can be incorporated to study voltage- or calcium-sensitive dyes that allow for the study of cardiomyocyte physiology [ 59 ]. Properties such as contraction can be assessed with relative pixel displacement or as absolute force of contraction [ 60 ].…”

“…Properties such as contraction can be assessed with relative pixel displacement or as absolute force of contraction [ 60 ]. Traction force microscopy can also be used in monolayered cell cultures [ 59 ].…”

Generation and Culture of Cardiac Microtissues in a Microfluidic Chip with a Reversible Open Top Enables Electrical Pacing, Dynamic Drug Dosing and Endothelial Cell Co-Culture

“…[19,20] Many OoC systems that recapitulate certain aspects of cardiac function, known as 'hearts-on-chips' (HoC), have been reported. [21,22] Integration of the advances in cardiac cell culture with HoC technology has been done on a 'fit-for-purpose' basis, where designs are guided by one specific aspect of cardiac physiology. Examples of this are HoCs with relatively simple mono-cultures that focus on electrophysiology [12,23,24] or on geometrical confinement.…”