Guiding the spatial organization of engineered heart tissues

The precise spatial organization of the heart across molecular, cellular, and tissue length scales underpins cardiac function. Recreating this architecture in engineered heart tissues remains a central challenge, as cardiac morphogenesis involves tightly coordinated, self-organizing programs governed by spatiotemporal biochemical, electrical, and mechanical cues. Although engineered cardiac systems have advanced substantially over the past two decades, most fail to recapitulate the dynamic spatial heterogeneity of the native myocardium. As a result, engineered constructs often exhibit immature phenotypes, impairing both tissue models and clinical applications. Here, we examine the principles and technologies that enable spatial control in cardiac tissue engineering. We first outline how spatial patterning arises in the native heart and distill design criteria relevant to engineered systems. Next, we summarize recent progress in the field including emerging applications of engineered heart tissues in organ-on-a-chip platforms and regenerative therapies. We then overview current approaches for guiding tissue organization, spanning biomolecular techniques that leverage morphogen gradients and multicellular signaling, electromechanical conditioning methods that promote cardiomyocyte alignment and maturation, and bioengineering platforms-including microfabrication, microfluidics, and bioprinting-that impose defined architectures and spatiotemporally controlled cues. We highlight how bottom-up self-organization and top-down engineering approaches are increasingly combined to generate hybrid systems that integrate user-defined structure with endogenous tissue assembly. Finally, we discuss the limitations of current-generation engineered tissues and speculate on future directions for the field, including adaptive and predictive design strategies. Collectively, these developments highlight spatial control as a central requirement for achieving the full capabilities of engineered cardiac tissues across basic and translational applications.