Our knowledge of the anatomy and physiology of the heart, as well as our ability to create synthetic ECM scaffolds have advanced to the point that valve replacement with nanofibrous scaffolds may be achieved in the short term, while myocardial repair requires further study in vitro and in vivo. We asked: Do we know enough to build a heart? To answer this question, we tabulated structural and functional properties of myocardial and valvular tissues for use as design criteria, reviewed nanofiber manufacturing platforms and assessed their capabilities to produce scaffolds that meet our design criteria. Here, we use the heart as a case study and examine the potential of ECM-inspired nanofibrous scaffolds for cardiac tissue engineering. Their high porosity, structural anisotropy, and bio-activity present unique advantages for engineering 3D anisotropic tissues. This can be achieved using nanofibrous scaffolds composed of polymers that simultaneously recapitulate 3D ECM architecture, high-fidelity nanoscale topography, and bio-activity. The design of regenerative three-dimensional (3D) engineered scaffolds is informed by the target ECM structure, chemistry, and mechanics, to encourage cell infiltration and tissue genesis. Natural ECMs therefore provide excellent design rules for tissue engineering scaffolds. From a biochemical perspective, factors regulating cell-ECM adhesion have been described and diverse aspects of cell-ECM interactions in health and disease continue to be clarified. The ECM promotes the interaction between individual cells and between different cell types, and increases the strength and resilience of the tissue in mechanically dynamic environments. From a structural perspective, the ECM is a scaffold that guides the self-assembly of cells into distinct functional tissues. Extracellular matrix (ECM) structure and biochemistry provide cell-instructive cues that promote and regulate tissue growth, function, and repair.
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