Melt Electrowriting Allows Tailored Microstructural and Mechanical Design of Scaffolds to Advance Functional Human Myocardial Tissue Formation

Abstract Engineering native‐like myocardial muscle, recapitulating its fibrillar organization and mechanical behavior is still a challenge. This study reports the rational design and fabrication of ultrastretchable microfiber scaffolds with controlled hexagonal microstructures via melt electrowriting (MEW). The resulting structures exhibit large biaxial deformations, up to 40% strain, and an unprecedented compliance, delivering up to 40 times more elastic energy than rudimentary MEW fiber scaffolds. Importantly, when human induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CM) are encapsulated in a collagen‐based hydrogel and seeded on these microstructured and mechanically tailored fiber scaffolds, they show an increase in beating rate (1.5‐fold), enhanced cell alignment, sarcomere content and organization as well as an increase in cardiac maturation‐related marker expression (Cx43 1.8‐fold, cardiac Actin 1.5‐fold, SERCA2a 2.5‐fold, KCNJ2 1.5‐fold, and PPARGC1a 3.6‐fold), indicative of enhanced iPSC‐CM maturation, as compared to rudimentary fiber scaffolds. By combining these novel fiber scaffolds with clinically relevant human iPSC‐CMs, a heart patch that allows further maturation of contractile myocytes for cardiac tissue engineering is generated. Moreover, the designed scaffold allows successful shape recovery after epicardial delivery on a beating porcine heart, without negative effects on the engineered construct and iPSC‐CM viability.