A unique bioreactor that offers synchronized physiological-like electrical and mechanical stimuli for cardiac tissue engineering

Abstract Cardiac tissue engineering aims to efficiently replace or repair injured heart tissue using scaffolds, relevant cells, or their combination. While the combination of scaffolds and relevant cells holds the potential to rapidly remuscularize the heart, thereby avoiding the slow process of cell recruitment, the proper ex vivo cellularization of a scaffold poses a substantial challenge. First, proper diffusion of nutrients and oxygen should be provided to the cell-seeded scaffold. Second, to generate a functional tissue construct, cells can benefit from physiological-like conditions. To meet these challenges, we developed a modular bioreactor for the dynamic cellularization of full-thickness cardiac scaffolds under synchronized mechanical and electrical stimuli. In this unique bioreactor system, we designed a cyclic mechanical load that mimics the left ventricle volume inflation, thus achieving a steady stimulus, as well as an electrical stimulus with an action potential profile to mirror the cells’ microenvironment and electrical stimuli in the heart. These mechanical and electrical stimuli were synchronized according to cardiac physiology and regulated by constant feedback. When applied to a seeded thick porcine cardiac extracellular matrix (pcECM) scaffold, these stimuli improved the proliferation of mesenchymal stem/stromal cells (MSCs) and induced the formation of a dense tissue-like structure near the scaffold’s surface. Most importantly, after 35 d of cultivation, the MSCs presented the early cardiac progenitor markers Connexin-43 and α-actinin, which were absent in the control cells. Overall, this research developed a new bioreactor system for cellularizing cardiac scaffolds under cardiac-like conditions, aiming to restore a sustainable dynamic living tissue that can bear the essential cardiac excitation–contraction coupling.