Dynamic Control of Contractile Force in Engineered Heart Tissue

Abstract

Three-dimensional engineered heart tissues (EHTs) derived from human induced pluripotent stem cells (iPSCs) have become an important resource for both drug toxicity screening and research on heart disease. A key metric of EHT phenotype is the contractile (twitch) force with which the tissue spontaneously beats. It is well-known that cardiac muscle contractility -its ability to do mechanical work -depends on tissue prestrain (preload) and external resistance (afterload). Objectives: Here, we demonstrate a technique to control afterload while monitoring contractile force exerted by EHTs. Methods: We developed an apparatus that can regulate EHT boundary conditions using real-time feedback control. The system is comprised of a pair of piezoelectric actuators that can strain the scaffold and a microscope that can measure EHT force and length. Closed loop control allows dynamic regulation of effective EHT boundary stiffness. Results: When controlled to switch instantaneously from auxotonic to isometric boundary conditions, EHT twitch force immediately doubled. Changes in EHT twitch force as a function of effective boundary stiffness were characterized and compared to twitch force in auxotonic conditions. Conclusion: EHT contractility can be regulated dynamically through feedback control of effective boundary stiffness. Significance: The capacity to alter the mechanical boundary conditions of an engineered tissue dynamically offers a new way to probe tissue mechanics. This could be used to mimic afterload changes that occur naturally in disease, or to improve mechanical techniques for EHT maturation.

High throughput screening system for engineered cardiac tissues

“…In prior work, the average peak contractile force for this geometry of µTug was about ∼100 µN and the average lateral micropillar stiffness was measured to be ∼5 μN/μm ( Legant et al, 2009 ; Hansen et al, 2010 ; Boudou et al, 2012 ; Spreeuwel et al, 2014 ; Polacheck and Chen, 2016 ; Mannhardt et al, 2017 ; Rocha et al, 2017 ; Thavandiran et al, 2020 ; Martins et al, 2021 ; Li et al, 2023 ). In the system reported here, the imaging resolution limit was about 10 μm, micropillar localization precision was 1 µm, and lateral stiffness of µTUG micropillars was averaged 5.3 μN/μm.…”

Contractility of cardiac and skeletal muscle tissue increases with environmental stiffness

“…Another study presented a system in which the boundary conditions of cardiac micro-tissue derived from human induced pluripotent stem cells (iPSCs) are regulated by real-time feedback control such that the pillars are pulled apart simultaneously with tissue contraction [28]. Under such near-isometric boundary conditions, contractile forces increased twofold compared to the unregulated condition, demonstrating that mechanoadaptation can be a very rapid process.…”

Multiscale mechanics of polydimethylsiloxane: A comparison of meso‐ and micro‐cyclic deformation behavior

“…The indentation process was recorded by a real‐time imaging endoscope to capture the probe‐pillar contact and indentation position. The Oliver & Pharr model was used to analyze the stiffness of μ‐pillar, where stiffness ( S , N/m) was calculated based on Equation 21,22 : where and represent absolute load and displacement change, respectively.…”

“…Beyond the single-cell level, advanced PDMS-based platforms have been extensively adopted to evaluate the contractile behaviors of engineered cardiac microbundles. 13,14,21,22 Nevertheless, the stress relaxation and strain hardening observed in the tensile testing of bulk PDMS samples raise concerns about the reliability of employing a single stiffness measurement of PDMS μ-pillars for predicting the contractile forces in cardiomyocytes and cardiac tissues. Therefore, we conducted cyclic indentation tests on PDMS μ-pillars.…”