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 maturationrelated 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.

Given their native-like biological properties, high growth factor retention capacity and porous nature, sulfated-polysaccharide-based scaffolds hold great promise for a number of tissue engineering applications. Specifically, as they mimic important properties of tissues such as bone and cartilage they are ideal for orthopaedic tissue engineering. Their biomimicry properties encompass important cell-binding motifs, native-like mechanical properties, designated sites for bone mineralization and strong growth factor binding and signalling capacity. Even so, scientists in the field have just recently begun to utilise them as building blocks for tissue engineering scaffolds. Most of these efforts have so far been directed towards in vitro studies, and for these reasons the clinical gap is still substantial. With this review paper, we have tried to highlight some of the important chemical, physical and biological features of sulfated-polysaccharides in relation to their chondrogenic and osteogenic inducing capacity. Additionally, their usage in various in vivo model systems is discussed. The clinical studies reviewed herein paint a promising picture heralding a brave new world for orthopaedic tissue engineering.

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