In the past few years, microfluidic-based technology has developed microscale models recapitulating key physical and biological cues typical of the native myocardium. However, the application of controlled physiological uniaxial cyclic strains on a defined three-dimension cellular environment is not yet possible. Two-dimension mechanical stimulation was particularly investigated, neglecting the complex three-dimensional cell-cell and cell-matrix interactions. For this purpose, we developed a heart-on-a-chip platform, which recapitulates the physiologic mechanical environment experienced by cells in the native myocardium. The device includes an array of hanging posts to confine cell-laden gels, and a pneumatic actuation system to induce homogeneous uniaxial cyclic strains to the 3D cell constructs during culture. The device was used to generate mature and highly functional micro-engineered cardiac tissues (μECTs), from both neonatal rat and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), strongly suggesting the robustness of our engineered cardiac micro-niche. Our results demonstrated that the cyclic strain was effectively highly uniaxial and uniformly transferred to cells in culture. As compared to control, stimulated μECTs showed superior cardiac differentiation, as well as electrical and mechanical coupling, owing to a remarkable increase in junction complexes. Mechanical stimulation also promoted early spontaneous synchronous beating and better contractile capability in response to electric pacing. Pacing analyses of hiPSC-CM constructs upon controlled administration of isoprenaline showed further promising applications of our platform in drug discovery, delivery and toxicology fields. The proposed heart-on-a-chip device represents a relevant step forward in the field, providing a standard functional three-dimensional cardiac model to possibly predict signs of hypertrophic changes in cardiac phenotype by mechanical and biochemical co-stimulation.

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We aim at testing the possibility to build patientspecific structural finite element models (FEMs) of the mitral valve (MV) from cardiac magnetic resonance (CMR) imaging and to use them to predict the outcome of mitral annuloplasty procedures. MV FEMs were built for one healthy subject and for one patient with ischemic mitral regurgitation. On both subjects, CMR imaging of 18 longaxis planes was performed with a temporal resolution of 55 time-frames per cardiac cycle. Three-dimensional MV annulus geometry, leaflets surface and PM position were manually obtained using custom software. Hyperelastic anisotropic mechanical properties were assigned to MV tissues. A physiological pressure load was applied to the leaflets to simulate valve closure until peak systole. For the pathological model only, a further simulation was run, simulating undersized rigid annuloplasty before valve closure. Closure dynamics, leaflets stresses and tensions in the subvalvular apparatus in the healthy MV were consistent with previous computational and experimental data. The regurgitant valve model captured with good approximation the real size and position of regurgitant areas at peak systole, and highlighted abnormal tensions in the annular region and sub-valvular apparatus. The simulation of undersized rigid annuloplasty showed the restoration of MV continence and normal tensions in the subvalvular apparatus and at the annulus. Our method seems suitable for implementing detailed patient-specific MV FEMs to simulate different scenarios of clinical interest. Further work is mandatory to test the method more deeply, to reduce its computational time and to expand the range of modeled surgical procedures.