Cardiac tissues generated from human induced pluripotent stem (iPS) cells can serve as platforms for patient-specific studies of physiology and disease1–6. The predictive power of these models remains limited by their immature state1,2,5,6. We show that this fundamental limitation could be overcome if cardiac tissues are formed from early iPS-derived cardiomyocytes (iPS-CM), soon after the initiation of spontaneous contractions, and subjected to physical conditioning of an increasing intensity. After only 4 weeks of culture, these tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiologic sarcomere length (2.2 μm) and density of mitochondria (30%), the presence of transverse tubules (t-tubules), oxidative metabolism, positive force-frequency relationship, and functional calcium handling for all iPS cell lines studied. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiologic responses to isoproterenol and recapitulating pathological hypertrophy, in support of the utility of this tissue model for studies of cardiac development and disease.

Graphical Abstract Highlights d Positive force frequency and post-rest potentiation are achieved in human tissues d Engineered atrial and ventricular tissues have distinct electrophysiology and drug responses d Atrio-ventricular tissues show spatially confined drug responses d Long-term electrical conditioning enables polygenic cardiac disease modeling SUMMARYTissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca 2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

Organs-on-a-chip (OOCs) are miniature tissues and organs grown in vitro that enable modeling of human physiology and disease. The technology has emerged from converging advances in tissue engineering, semiconductor fabrication, and human cell sourcing. Encompassing innovations in human stem cell technology, OOCs offer a promising approach to emulate human patho/physiology in vitro, and address limitations of current cell and animal models. Here, we review the design considerations for single and multi-organ OOCs, discuss remaining challenges, and highlight the potential impact of OOCs as a fast-track opportunity for tissue engineering to advance drug development and precision medicine.

The organ-on-a-chip (OoC) is an intriguing scientific and technological development in which biology is coupled with microtechnology 1,2 to mimic key aspects of human physiology. The chip takes the form of a microfluidic device containing networks of hair-fine microchannels for guiding and manipulating minute volumes (picolitres up to millilitres) of solution [3][4][5] . The organ is a more relatable term that refers to the miniature tissues grown and residing in the microfluidic chips, which can recapitulate one or more tissue-specific functions. Although they are much simpler than native tissues and organs, scientists have discovered that these systems can often serve as effective mimics of human physiology and disease. OoCs comprise advanced in vitro technology that enables experimentation with biological cells and tissues outside the body. This is achieved by containing them inside vessels conditioned to sustain a reasonable semblance of the in vivo environment, from a biochemical and physical point of view. Working on the microscale lends a unique opportunity to attain a higher level of control over the microenvironment that ensures tissue life support, as well as a means to directly observe cell and tissue behaviour.The OoC is a relatively recent addition to the toolbox of model biological systems available to life science researchers to probe aspects of human pathophysiology and disease. These systems cover a spectrum of physiological relevance, with 2D cell cultures the least relevant, followed in increasing order by 3D cell cultures, organoids and OoCs. Unsurprisingly, the use of model organisms such as mice and Drosophila physiologically exceeds engineered tissue approaches 6,7 . While biological complexity increases with physiological relevance in model organisms, this unfortunately leads to increased experimental difficulty. In vivo physiological processes are, in many ways, the least accessible to direct investigation in mice, humans and other mammals, despite significant advances in in vivo imaging. However, 2D and 3D cell cultures, such as spheroids and stem cell-derived organoids, sacrifice some aspects of in vivo relevance to facilitate experimentation. The OoC may be regarded as a bridging technology, offering the ability to work with complex cell cultures, while providing better engineered microenvironments to maximize the model.Following on from early concepts, including animal-on-a-chip 8 , body-on-a-chip 9 and breathing lung-on-a-chip 10 , research in the OoC and microphysiological systems fields has grown exponentially; evidenced by numerous excellent reviews published recently 1,2,11 . Recognition of OoC technology now extends far beyond university laboratories, driven by a need to better understand the human physiology underlying health and disease, and to find new approaches to improve the human condition. The World Economic Forum, for instance, selected the OoC as one of the top ten emerging technologies in 2016 (ref. 12

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Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma...