Biologically-inspired melt electrowriting for the generation of highly biomimetic functional myocardium

In the heart, the specific 3D structure of myocardial layers produces an efficient ejection of blood. When myocardial infarction strikes, this architecture is disrupted, adding a disarranged contraction to the decreased availability of pumping units (cardiomyocytes, CMs). In this work, we characterize the alignment of cardiac fibers in a large animal model (pig) and employ melt electrowriting (MEW) to fabricate a bio-inspired scaffold with diamond-shaped pores. Using human induced pluripotent stem cell-derived CMs and cardiac fibroblasts, we generate human cardiac tissues with a biomimetic in-plane contraction. Our tissues beat macroscopically for over one month, with significantly faster kinetics, increased force and higher conduction velocity than those based on square or rectangular pores. Our diamond design induces a specific hiPSC-CM alignment resulting in the observed in-plane contraction. Transcriptomic analysis using bulk RNA-seq reveals diamond-MEW tissues present features of maturation as compared to traditional 2D cultures. Finally, we employ the bio-inspired cardiac tissues to treat an infarction model in athymic rats, showing a significant benefit on systolic function and remodeling, tied to the presence of large grafts of human cells remuscularizing the ventricular wall. All in all, we demonstrate that the new design generates superior human cardiac tissues with therapeutic capacity.