Dynamic Control of Contractile Force in Engineered Heart Tissue

Abstract

<p>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 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 both preload and afterload dynamically while monitoring contractile force exerted by EHTs. Methods: We developed an apparatus that uses real-time feedback control to monitor and regulate EHT forces. The system is comprised of a pair of high-speed piezoelectric actuators that can strain the EHT scaffold and a fast optical measurement tool to provide EHT contractile force feedback while monitoring tissue strain. Results: The system was used to regulate the effective stiffness of the scaffold. When controlled to have effectively isometric boundary conditions, EHTs exerted a contractile force that was almost twice as large as that observed under auxotonic conditions. Conclusion: These experimental results demonstrate that EHT contractility can be increased through feedback control to regulate boundary stiffness. Significance: The work advances our understanding of the role that mechanical environment plays in EHT contractility. This could be used to help study or alter EHT phenotype and potentially EHT maturation through controlled mechanical conditioning.</p>