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.

No abstract

Myocardial fibrosis is a severe global health problem due to its prevalence in all forms of cardiac diseases and direct role in causing heart failure. The discovery of efficient antifibrotic compounds has been hampered due to the lack of a physiologically relevant disease model. Herein, we present a disease model of human myocardial fibrosis and use it to establish a compound screening system. In the Biowire II platform, cardiac tissues are suspended between a pair of poly(octamethylene maleate (anhydride) citrate) (POMaC) wires. Noninvasive functional readouts are realized on the basis of the deflection of the intrinsically fluorescent polymer. The disease model is constructed to recapitulate contractile, biomechanical, and electrophysiological complexities of fibrotic myocardium. Additionally, we constructed a heteropolar integrated model with fibrotic and healthy cardiac tissues coupled together. The integrated model captures the regional heterogeneity of scar lesion, border zone, and adjacent healthy myocardium. Finally, we demonstrate the utility of the system for the evaluation of antifibrotic compounds. The high-fidelity in vitro model system combined with convenient functional readouts could potentially facilitate the development of precision medicine strategies for cardiac fibrosis modeling and establish a pipeline for preclinical compound screening.

Tumor progression relies on the interaction between neoplastic epithelial cells and their surrounding stromal partners. This cell cross-talk affects stromal development, and ultimately the heterogeneity impacts drug efficacy. To mimic this evolving paradigm, 3D vascularized pancreatic adenocarcinoma tissue is microengineered in a tri-culture system composed of patient-derived pancreatic organoids, human fibroblasts, and endothelial cells on a perfusable platform, situated in a 96-well plate. Through synergistic engineering, the benefits of cellular fidelity of patient tumor organoids are combined with the flow control of an organ-on-a-chip platform. Validation of this platform includes demonstrating the growth of pancreatic tumor organoids by monitoring the change in metabolic activity of the tissue. Investigation of the tumor microenvironment highlights the role of fibroblasts in symbiosis with patient organoids, resulting in a sixfold increase of collagen deposition and corresponding increase in tissue stiffness in comparison to fibroblast free controls. The value of a perfusable vascular network is evident in drug screening, as perfusing gemcitabine into stiffened matrix does not show the dose-dependent effects on decrease in tumor viability as those under static conditions. These findings demonstrate the importance of a dynamic synergistic relationship between patient cells with stromal fibroblasts, in a 3D perfused vascular network, to accurately recapitulate a dynamic tumor microenvironment.

No abstract