Leaf-venation-directed cellular alignment for macroscale cardiac constructs with tissue-like functionalities

Recapitulating the complex structural, mechanical, and electrophysiological properties of native myocardium is crucial to engineering functional cardiac tissues. Here, we report a leaf-venation-directed strategy that enables the compaction and remodeling of cell-hydrogel hybrids into highly aligned and densely packed organizations in predetermined patterns. This strategy contributes to interconnected tubular structures with cell alignment along the hierarchical channels. Compared to randomly-distributed cells, the engineered leaf-venation-directed-cardiac tissues from neonatal rat cardiomyocytes manifest advanced maturation and functionality as evidenced by detectable electrophysiological activity, macroscopically synchronous contractions, and upregulated maturation genes. As a demonstration, human induced pluripotent stem cell-derived leaf-venation-directed-cardiac tissues are engineered with evident structural and functional improvement over time. With the elastic scaffolds, leaf-venation-directed tissues are assembled into 3D centimeter-scale cardiac constructs with programmed mechanical properties, which can be delivered through tubing without affecting cell viability. The present strategy may generate cardiac constructs with multifaceted functionalities to meet clinical demands.