Toward Origami-Inspired In Vitro Cardiac Tissue Models

The advancement of <i>in vitro</i> engineered cardiac tissue-based patches is paramount for providing viable solutions for restoring cardiac function through <i>in vivo</i> implantation. Numerous techniques described in the literature aim to provide diverse mechanical and topographical cues simultaneously, fostering enhanced <i>in vitro</i> cardiac maturation and functionality. Among these, cellulose paper-based scaffolds have gained attention owing to their inherent benefits, such as biocompatibility and ease of chemical and physical modification. This study introduces a novel approach of utilizing customized paper-based scaffolds as cell culture substrates, facilitating both the formation and manipulation of cell constructs while promoting mechanical contraction. Here, we investigated two methodologies to foster mechanical contractions of paper-based constructs: the incorporation of micropatterns on paper to dictate cell orientation and macropattern created by the origami-folded paper. Both approaches provide mechanical support and foster cardiac functionality. However, while micropatterning does not significantly improve the functional parameters, a macropattern created by origami folding proves to be essential in facilitating contraction of the paper-based cardiac constructs. Furthermore, we provide proof of principle for the combination with a layer of physiologically differentiated microvascular networks. This approach holds great promise for the development of structurally organized contractile cardiac tissues with the possibility of creating multistrata of cardiac and vascular layers to promote <i>in vivo</i> cell survival and function beyond what is typically achieved in conventional cell culture.