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

Engineering functional cardiac tissues would represent a therapeutic alternative for patients with end-stage heart disease. Recapitulating the complex structural, mechanical, and electrophysiological properties of the heart is crucial to improving the utility of the engineered cardiac tissues. Here, we report a leaf-venation-directed strategy that enables the contraction and remodeling of cell-hydrogel hybrids into a highly aligned and densely packed organization in predetermined patterns. This strategy contributes to biomimetic hierarchical vasculatures with interconnected tubular structures and the improved maturation and functionality of the engineered rat and human cardiac tissues, evidenced by robust electrophysiological activity, macroscopically synchronous contractions, and upregulation of crucial maturation genes. With the mechanical support of the elastic scaffolds, functional leaf-venation-directed tissues can be assembled into 3D pre-vascularized cardiac constructs resembling the anisotropic mechanical properties of native myocardium and allowing for minimally invasive implantation. The present strategy may generate cardiac tissue constructs with multifaceted functionalities to meet clinical demands.