Toward a Physiologically Relevant 3D Helicoidal-Oriented Cardiac Model: Simultaneous Application of Mechanical Stimulation and Surface Topography
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Author
Navaee, Fatemeh
Renaud, Philippe
Piacentini, Niccolo
Durand, Mathilde
Bayat, Dara Zaman
Ledroit, Diane
Boder-Pasche, Stéphanie
Kleger, Alexander
Braschler, Thomas
Weder, Gilles
Abstract
Myocardium consists of cardiac cells that interact with their environment through physical,
biochemical, and electrical stimulations. The physiology, function, and metabolism of cardiac tissue
are affected by this dynamic structure. Within the myocardium, cardiomyocytes’ orientations are
parallel, creating a dominant orientation. Additionally, local alignments of fibers, along with a helical
organization, become evident at the macroscopic level. For the successful development of a reliable
in vitro cardiac model, evaluation of cardiac cells’ behavior in a dynamic microenvironment, as well
as their spatial architecture, is mandatory. In this study, we hypothesize that complex interactions
between long-term contraction boundary conditions and cyclic mechanical stimulation may provide
a physiological mechanism to generate off-axis alignments in the preferred mechanical stretch
direction. This off-axis alignment can be engineered in vitro and, most importantly, mirrors the
helical arrangements observed in vivo. For this purpose, uniaxial mechanical stretching of dECMfibrin
hydrogels was performed on pre-aligned 3D cultures of cardiac cells. In view of the potential
development of helical structures similar to those in native hearts, the possibility of generating
oblique alignments ranging between 0 and 90 was explored. Indeed, our investigations of cell
alignment in 3D, employing both mechanical stimulation and groove constraint, provide a reliable
mechanism for the generation of helicoidal structures in the myocardium. By combining cyclic stretch
and geometric alignment in grooves, an intermediate angle toward favored direction can be achieved
experimentally: while cyclic stretch produces a perpendicular orientation, geometric alignment is
associated with a parallel one. In our 2D and 3D culture conditions, nonlinear cellular addition of
the strains and strain avoidance concept reliably predicted the preferred cellular alignment. The
3D dECM-fibrin model system in this study shows that cyclical stretching supports cell survival
and development. Using mechanical stimulation of pre-aligned heart cells, maturation markers are
augmented in neonatal cardiomyocytes, while the beating culture period is prolonged, indicating an
improved model function. We propose a simplified theoretical model based on numerical simulation
and nonlinear strain avoidance by cells to explain oblique alignment angles. Thus, this work lays a
possible rational basis for understanding and engineering oblique cellular alignments, such as the
helicoidal layout of the heart, using approaches that simultaneously enhance maturation and function.
Publication Reference
Bioengineering 2023, 10, 266
Year
2023-02-17